Oxadiazoanthracene Compounds for the Treatment of Diabetes

ABSTRACT

The present invention provides methods of use of oxadiazoanthracene derivatives of the formula (I) and pharmaceutically acceptable salts thereof, 
     
       
         
         
             
             
         
       
     
     wherein A, B, C, R, R 1 , R 2 , R 3 , R 4  and R 5  are as herein described, and wherein said methods of use include uses for the treatment of disorders and diseases, such as diabetes.

BACKGROUND OF THE INVENTION

The present invention provides oxadiazoanthracene derivatives,compositions comprising oxadiazoanthracene derivatives, use of theoxadiazoanthracene derivatives for the preparation of pharmaceuticalcompositions and methods of use thereof for the treatment and/orprevention of disorders and diseases wherein modulation of the humanGLP-1 receptor is beneficial.

Type II diabetes mellitus is a metabolic disorder where diseaseprogression may be characterized by peripheral tissue insulinresistance, hyperglycemia, islet b-cell compensation, hyperinsulinemia,dyslipidemia, increased liver gluconeogenesis and ultimate loss ofb-cell mass and function. The pathophysiological consequences ofaberrant glucose and lipid metabolism are toxicity to organs such as,but not limited to, the kidney, eye, peripheral neurons, vasculature andheart. Thus, there is a medical need for agents that may delay diseaseprogression by improving glycemic control and b-cell mass and function.

Glucagon-like peptide-1 (GLP-1) is a member of the incretin family ofneuroendocrine peptide hormones secreted from L-cells of the intestinein response to food ingestion. GLP-1 has multiple metabolic effects thatare attractive for an anti-diabetic agent. A key function of GLP-1 is toactivate its receptor, GLP-1R, on the pancreatic b-cell to enhanceglucose-dependent insulin secretion. Positive metabolic benefits ofGLP-1 may include, but are not limited to, suppression of excessiveglucagon production, decreased food intake, delayed gastric emptying,and improvement of b-cell mass and function. The positive effects ofGLP-1 on b-cell mass and function offers the hope that GLP-1-basedtherapies may delay early stage disease progression. In addition, aGLP-1 agonist could be useful in combination therapies such as withinsulin in patients with type I diabetes. Unfortunately, the rapidproteolysis of GLP-1 into an inactive metabolite limits its use as atherapeutic agent.

Validation of GLP-1R agonists as a therapeutic modality was achieved byExendin-4 (Byetta® (Amylin Pharmaceuticals, Inc.)), a peptide GLP-1receptor agonist recently approved for the treatment of Type II diabetesmellitus. Dosing of Exendin-4 by subcutaneous administration lowersblood glucose and decreases HbA1c levels, which are important biomarkermeasurements for disease control. Therefore, an oral GLP-1 receptoragonist should provide glycemic control while offering the convenienceof oral dosing.

GLP-1R belongs to the class B receptor sub-class of the Gprotein-coupled receptor (GPCR) superfamily that regulates manyimportant physiological and pathophysiological processes. In addition tothe seven transmembrane domains characteristic of all GPCR familymembers, class B GPCRs contain a relatively large N-terminal domain. Itis believed the binding and activation of these receptors by relativelylarge natural peptide ligands require both the N-terminal domain and thetransmembrane domain of the receptor. In particular, class B GPCRs haveproven difficult for the identification of low molecular weightnon-peptide agonist molecules.

Because peptides, such as GLP-1, may lack sufficient oralbioavailability for consideration as oral drug agents, small moleculemodulators of GLP-1R with oral bioavailability are highly desired. Thepresent invention describes a class of compounds that modulate GLP-1R.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula (I), or apharmaceutically acceptable salt thereof, methods comprising the use ofcompounds of formula (I), or a pharmaceutically acceptable salt thereof,for the preparation of pharmaceutical compositions, methods comprisingthe use of compounds of formula (I), or a pharmaceutically acceptablesalt thereof, for the treatment and/or prevention of disorders anddiseases, and pharmaceutical compositions comprising compounds offormula (I), or a pharmaceutically acceptable salt thereof,

wherein A, B, C, R, R¹, R², R³, R⁴ and R⁵ are as herein described.

The present invention further relates to intermediates useful, forexample, in the synthesis of compounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following definitions are meant to clarify, but not limit, the termsdefined. If a particular term used herein is not specifically defined,such term should not be considered indefinite. Rather, terms are usedwithin their ordinary meanings

As used herein the term “alkyl” refers to a straight or branched chainhydrocarbon having one to twelve carbon atoms, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. Examples of “alkyl” as used herein include,but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,n-butyl, tert-butyl, isopentyl, and n-pentyl.

As used throughout this specification, the number of atoms, such ascarbon atoms in an alkyl group, for example, will be represented by thephrase “C_(x)-C_(y) alkyl,” or “C_(x-y) alkyl,” which refer to an alkylgroup, as herein defined, containing from x to y, inclusive, carbonatoms. Similar terminology will apply for other terms and ranges aswell. One embodiment of the present invention includes so-called ‘lower’alkyl chains of one to six carbon atoms. Thus, C₁-C₆ alkyl represents alower alkyl chain as hereabove described.

As used herein the term “alkenyl” refers to a straight or branched chainaliphatic hydrocarbon having two to twelve carbon atoms and containingone or more carbon-to-carbon double bonds, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. Examples of “alkenyl” as used hereininclude, but are not limited to, vinyl, and allyl.

As used herein the term “alkynyl” refers to a straight or branched chainaliphatic hydrocarbon having two to twelve carbon atoms and containingone or more carbon-to-carbon triple bonds, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. An example of “alkynyl” as used hereinincludes, but is not limited to, ethynyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,which may be optionally substituted as herein further described, withmultiple degrees of substitution being allowed. Examples of “alkylene”as used herein include, but are not limited to, methylene, ethylene,n-propylene, and n-butylene.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand containing one or more carbon-to-carbon double bonds, which may beoptionally substituted as herein further described, with multipledegrees of substitution being allowed. Examples of “alkenylene” as usedherein include, but are not limited to, vinylene, allylene, and2-propenylene.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand containing one or more carbon-to-carbon triple bonds, which may beoptionally substituted as herein further described, with multipledegrees of substitution being allowed. An example of “alkynylene” asused herein includes, but is not limited to, ethynylene.

As used herein, the term “alkoxy” refers to the group R^(x)O—, whereR^(x) is alkyl.

As used herein, the term “alkenyloxy” refers to the group R^(x)O—, whereR^(x) is alkenyl.

As used herein, the term “alkynyloxy” refers to the group R^(x)O—, whereR^(x) is alkynyl.

As used herein, the term “alkylsulfanyl” refers to the group R^(x)S—,where R^(x) is alkyl.

As used herein, the term “alkenylsulfanyl” refers to the group R^(x)S—,where R^(x) is alkenyl.

As used herein, the term “alkynylsulfanyl” refers to the group R^(x)S—,where R^(x) is alkynyl.

As used herein, the term “alkylsulfinyl” refers to the group R^(x)S(O)—,where R^(x) is alkyl.

As used herein, the term “alkenylsulfinyl” refers to the groupR^(x)S(O)—, where R^(x) is alkenyl.

As used herein, the term “alkynylsulfinyl” refers to the groupR^(x)S(O)—, where R^(x) is alkynyl.

As used herein, the term “alkylsulfonyl” refers to the group R^(x)SO₂—,where R^(x) is alkyl.

As used herein, the term “alkenylsulfonyl” refers to the groupR^(x)SO₂—, where R^(x) is alkenyl.

As used herein, the term “alkynylsulfonyl” refers to the groupR^(x)SO₂—, where R^(x) is alkynyl.

As used herein, the term “cycloalkyl” refers to an optionallysubstituted non-aromatic, three- to twelve-membered, cyclic hydrocarbonring, optionally containing one or more degrees of unsaturation, whichmay be optionally substituted as herein further described, with multipledegrees of substitution being allowed. Exemplary “cycloalkyl” groups asused herein include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl, as well as rings containingone or more degrees of unsaturation but short of aromatic, such ascyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, andcycloheptenyl.

As used herein, the term “cycloalkylene” refers to a divalent,non-aromatic, three- to twelve membered, cyclic hydrocarbon ring, whichmay be optionally substituted as herein further described, with multipledegrees of substitution being allowed. Exemplary “cycloalkylene” groupsinclude, but are not limited to, cyclopropylene, cyclobutylene,cyclopentylene, cyclohexylene, cycloheptylene, and substituted versionsthereof. The term is intended to encompass divalent rings havingdifferent points of attachment as well as a common point of attachment,which connecting atom may also be referred to as “spiroatom.”

As used herein, the terms “heterocyclic”, “heterocycle”, and“heterocyclyl” refers to an optionally substituted univalentnon-aromatic mono- or polycyclic ring system, optionally containing oneor more degrees of unsaturation and also containing one or moreheteroatoms selected from the group consisting of nitrogen, oxygen, andsulfur, which may be optionally substituted, including oxidized, asherein further described, with multiple degrees of substitution beingallowed. Typically, the ring is three to twelve-membered and is eitherfully saturated or has one or more degrees of unsaturation. Such ringsmay be optionally fused to one or more of another heterocyclic ring(s),cycloalkyl ring(s), aryl groups (as defined below) or heteroaryl groups(as defined below). Examples of “heterocyclic” groups as used hereininclude, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane,1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,and tetrahydrothiophene.

As used herein, the term “heterocyclylene” refers to an optionallysubstituted non-aromatic diradical ring system, optionally containingone or more degrees of unsaturation and also containing one or moreheteroatoms, selected from the group consisting of nitrogen, oxygen, andsulfur, which may be optionally substituted, including oxidized, asherein further described, with multiple degrees of substitution beingallowed. Typically, the ring is three to twelve-membered and is eitherfully saturated or has one or more degrees of unsaturation. Such ringsmay be optionally fused to one or more of another heterocyclic ring(s),cycloalkyl ring(s), aryl groups (as defined below) or heteroaryl groups(as defined below). Examples of “heterocyclylene” include, but are notlimited to, tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, andpyran-2,4-diyl.

As used herein, the term “aryl” refers to a univalent aromatic carboncontaining ring or polycyclic fused ring system (up to three rings)where each ring contains between 3 to 7 atoms, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. Examples of “aryl” groups as used include,but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, anthracene,phenanthrene, and indene.

As used herein, the term “arylene” refers to a divalent aromatic carboncontaining ring or polycyclic fused ring system (up to three rings)where each ring contains between 3 to 7 atoms, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. Examples of “arylene” include, but are notlimited to, benzene-1,4-diyl, naphthalene-1,8-diyl.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such aromatic rings, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. These heteroaryl rings contain one or morenitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. Examples of“heteroaryl” groups as used herein include, but should not be limitedto, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline,benzofuran, benzodioxolyl, benzothiophene, indole, indazole,benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl.

As used herein, the term “heteroarylene” refers to a monocyclic five- toseven-membered aromatic ring diradical, or to a fused bicyclic ringsystem comprising two such rings, which may be optionally substituted asherein further described, with multiple degrees of substitution beingallowed. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxides arepermissible heteroatom substitutions. Examples of “heteroarylene” usedherein include, but are not limited to, furan-2,5-diyl,thiophene-2,4-diyl, and pyridine-2,4-diyl.

As used herein, the term “fused cycloalkylaryl” refers to one or twocycloalkyl groups fused to an aryl group, the aryl and cycloalkyl groupshaving two atoms in common, and wherein the aryl group is the point ofsubstitution. Examples of “fused cycloalkylaryl” used herein include5-indanyl, and 5,6,7,8-tetrahydro-2-naphthyl

As used herein, the term “fused cycloalkylarylene” refers to a fusedcycloalkylaryl, wherein the aryl group is divalent. Examples include

As used herein, the term “fused arylcycloalkyl” refers to one or twoaryl groups fused to a cycloalkyl group, the cycloalkyl and aryl groupshaving two atoms in common, and wherein the cycloalkyl group is thepoint of substitution. Examples of “fused arylcycloalkyl” used hereininclude 1-indanyl, 2-indanyl, 9-fluorenyl,1-(1,2,3,4-tetrahydronaphthyl) and

As used herein, the term “fused arylcycloalkylene” refers to a fusedarylcycloalkyl, wherein the cycloalkyl group is divalent. Examplesinclude 9,1-fluorenylene

As used herein, the term “fused heterocyclylaryl” refers to one or twoheterocyclyl groups fused to an aryl group, the aryl and heterocyclylgroups having two atoms in common, and wherein the aryl group is thepoint of substitution. Examples of “fused heterocyclylaryl” used hereininclude 3,4-methylenedioxy-1-phenyl and

As used herein, the term “fused heterocyclylarylene” refers to a fusedheterocyclylaryl, wherein the aryl group is divalent. Examples include

As used herein, the term “fused arylheterocyclyl” refers to one or twoaryl groups fused to a heterocyclyl group, the heterocyclyl and arylgroups having two atoms in common, and wherein the heterocyclyl group isthe point of substitution. Examples of “fused arylheterocyclyl” usedherein include 2-(1,3-benzodioxolyl) and

As used herein, the term “fused arylheterocyclylene” refers to a fusedarylheterocyclyl, wherein the heterocyclyl group is divalent. Examplesinclude

As used herein, the term “fused cycloalkylheteroaryl” refers to one ortwo cycloalkyl groups fused to a heteroaryl group, the heteroaryl andcycloalkyl groups having two atoms in common, and wherein the heteroarylgroup is the point of substitution. Examples of “fusedcycloalkylheteroaryl” used herein include 5-aza-6-indanyl and

As used herein, the term “fused cycloalkylheteroarylene” refers to afused cycloalkylheteroaryl, wherein the heteroaryl group is divalent.Examples include

As used herein, the term “fused heteroarylcycloalkyl” refers to one ortwo heteroaryl groups fused to a cycloalkyl group, the cycloalkyl andheteroaryl groups having two atoms in common, and wherein the cycloalkylgroup is the point of substitution. Examples of “fusedheteroarylcycloalkyl” used herein include 5-aza-1-indanyl and

As used herein, the term “fused heteroarylcycloalkylene” refers to afused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent.Examples include

As used herein, the term “fused heterocyclylheteroaryl” refers to one ortwo heterocyclyl groups fused to a heteroaryl group, the heteroaryl andheterocyclyl groups having two atoms in common, and wherein theheteroaryl group is the point of substitution. Examples of “fusedheterocyclylheteroaryl” used herein include1,2,3,4-tetrahydro-beta-carbolin-8-yl and

As used herein, the term “fused heterocyclylheteroarylene” refers to afused heterocyclylheteroaryl, wherein the heteroaryl group is divalent.Examples include

As used herein, the term “fused heteroarylheterocyclyl” refers to one ortwo heteroaryl groups fused to a heterocyclyl group, the heterocyclyland heteroaryl groups having two atoms in common, and wherein theheterocyclyl group is the point of substitution. Examples of “fusedheteroarylheterocyclyl” used herein include-5-aza-2,3-dihydrobenzofuran-2-yl and

As used herein, the term “fused heteroarylheterocyclylene” refers to afused heteroarylheterocyclyl, wherein the heterocyclyl group isdivalent. Examples include

As used herein, the term “acyl” refers to the group R^(x)C(O)—, whereR^(x) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyl” refers to the group R^(x)C(O)—, whereR^(x) is aryl.

As used herein, the term “heteroaroyl” refers to the group R^(x)C(O)—,where R^(x) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR^(x)OC(O)—, where R^(x) is alkyl.

As used herein, the term “acyloxy” refers to the group R^(x)C(O)O—,where R^(x) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyloxy” refers to the group R^(x)C(O)O—,where R^(x) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR^(x)C(O)O—, where R^(x) is heteroaryl.

As used herein the term “halogen” refers to fluorine, chlorine, bromine,or iodine.

As used herein the term “haloalkyl” refers to an alkyl group, as definedherein, that is substituted with at least one halogen. Examples ofbranched or straight chained “haloalkyl” groups as used herein include,but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, andt-butyl substituted independently with one or more halogens, forexample, fluoro, chloro, bromo, and iodo. The term “haloalkyl” should beinterpreted to include such substituents as perfluoroalkyl groups suchas —CF₃.

As used herein, the term “haloalkylene” refers to a straight or branchedchain divalent hydrocarbon radical, substituted with at least onehalogen. The term should be interpreted to include perfluoroalkylenegroups such as —CF₂—.

As used herein, the term “haloalkoxy” refers to a group —OR^(x), whereR^(x) is a haloalkyl group as herein defined. As non-limiting examples,haloalkoxy groups include —O(CH₂)F, —O(CH)F₂, and —OCF₃.

As used herein the term “nitro” refers to a group —NO₂.

As used herein the term “cyano” refers to a group —CN.

As used herein the term “azido” refers to a group —N₃.

As used herein the term “amide” refers to a group —C(O)NR^(x)R^(y) or—NR^(x)C(O)—, where each R^(x) and R^(y) individually is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocylcyl, or heteroaryl.

As used herein “amino” refers to a group —NR^(x)R^(y), where each ofR^(x) and R^(y) individually is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heterocylcyl, or heteroaryl.

As used herein, when either R^(x) or R^(y) is other than hydrogen, sucha group may be referred to as a “substituted amino” or, for example ifR^(x) is H and R^(y) is alkyl, as an “alkylamino.”

As used herein, the term “oxo” shall refer to the substituent ═O, and isavailable as a substituent on carbon atoms have at least two hydrogensavailable for substitution and on heteroatoms such as nitrogen andsulfur where the heteroatom may be oxidized to form a bond with the oxosubstituent.

As used herein, the terms “hydroxy” and “hydroxyl” refer to a group —OH.

As used herein, the term “aminosulfonyl” refers to the substituent—SO₂NH₂.

As used herein, the term “mercapto” refers to the substituent —SH.

As used herein, the terms “carboxy” and “carboxyl” refer to thesubstituent —COOH.

As used herein, the term “carbamoyl” refers to the substituent —C(O)NH₂.

As used herein, the term “sulfanyl” refers to the substituent —S—.

As used herein, the term “sulfinyl” refers to the substituent —S(O)—.

As used herein, the term “sulfonyl” refers to the substituent —S(O)₂—.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur.

As used herein, the term “direct bond”, where part of a structuralvariable specification, refers to the direct joining of the substituentsflanking (preceding and succeeding) the variable taken as a “directbond”. Where two or more consecutive variables are specified each as a“direct bond”, those substituents flanking (preceding and succeeding)those two or more consecutive specified “direct bonds” are directlyjoined.

As used herein, the term “substituted” refers to substitution of one ormore hydrogens of the designated moiety with the named substituent orsubstituents, multiple degrees of substitution being allowed unlessotherwise stated, provided that the substitution results in a stable orchemically feasible compound. A stable compound or chemically feasiblecompound is one in which the chemical structure is not substantiallyaltered when kept at a temperature from about −80° C. to about +40° C.,in the absence of moisture or other chemically reactive conditions, forat least a week, or a compound which maintains its integrity long enoughto be useful for therapeutic or prophylactic administration to apatient.

As used herein, the phrase “one or more substituents” refers to a numberof substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met.

As used herein the terms “pharmaceutically acceptable carrier”,“pharmaceutically acceptable diluent”, and pharmaceutically acceptableexcipient” means the carrier, diluent or excipient must be compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof.

As used herein the term “therapeutically effective amount” as usedherein means that amount of active compound or pharmaceutical agent thatelicits the biological or medicinal response in a tissue, system,animal, human, or subject that is being sought by a researcher,veterinarian, medical doctor, patient or other clinician, which includesreduction or alleviation of the symptoms of the disease being treated.When the active compound (i.e., active ingredient) is administered asthe salt, references to the amount of active ingredient are to the freeacid or free base form of the compound.

As used herein, “Subject(s)” include, for example, horses, cows, sheep,pigs, mice, dogs, cats, primates such as chimpanzees, gorillas, rhesusmonkeys, and, humans. In one embodiment, a subject is a human. Inanother embodiment, a subject is a human in need of activation ofGLP-1R.

Compounds

Embodiments of the present invention comprise substitutedtetrahydroisoquinoline derivatives, compositions, and methods of usethereof. The present invention may be embodied in a variety of ways.

In a first aspect, the present invention provides tetrahydroisoquinolinederivatives which are modulators of GLP-1R which may be useful for themanagement and treatment of disease where modulation of the human GLP-1receptor is beneficial.

In a first exemplary embodiment, the present invention provides acompound of Formula (I):

wherein

-   R is —(CH₂)_(p)-G¹-L¹-G², wherein    -   L¹ is selected from the group consisting of: a direct bond,        —CH₂—, —O—, —N(R¹⁶)—, —C(O)—, —CON(R¹⁶)—, —N(R¹⁶)C(O)—,        —N(R¹⁶)SO₂—, —SO₂N(R¹⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—,        —S(O)₂—, and —C≡C—, wherein        -   R¹⁶ is selected from the group consisting of: -hydrogen,            -alkyl, -aryl, -alkylene-aryl;    -   G¹ is selected from the group consisting of: alkynylene,        arylene, heteroarylene, fused arylcycloalkylene, fused        cycloalkylarylene, fused cycloalkylheteroarylene, fused        heterocyclylarylene, and fused heterocyclylheteroarylene,        wherein G¹ is optionally substituted 1-4 times with substituents        independently selected from R¹⁰, wherein        -   R¹⁰ is R^(b),    -   G² is selected from the group consisting of: -aryl, -heteroaryl,        -fused arylcycloalkyl, -fused cycloalkylaryl, -fused        cycloalkylheteroaryl, -fused heterocyclylaryl, and -fused        heterocyclylheteroaryl, wherein G² is optionally substituted 1-4        times with substituents independently selected from R¹¹, wherein        -   R¹¹ is R^(b),-   R¹ is selected from the group consisting of: —CO₂H, —CO₂R¹²,    —C(O)NH₂, —C(O)NHR¹², -tetrazole, and acid isostere, wherein    -   R¹² is selected from the group consisting of: —C₁₋₁₀ alkyl,        -cycloalkyl, and -aryl, wherein R¹² is optionally substituted        1-4 times with a group independently selected from R^(c);-   R² is selected from the group consisting of: -hydrogen, -alkyl,    -phenyl, -cycloalkyl, -alkylene-cycloalkyl, and -alkylene-phenyl,    wherein alkyl, phenyl, and cycloalkyl groups are optionally    substituted 1-4 times with a group independently selected from R^(c)-   R³ is selected from R^(a);-   R⁴ is selected from R^(a); and-   R⁵ is -G³-L²-Q²-L³-G⁴, wherein    -   L² and L³ are independently selected from the group consisting        of: a direct bond, —CH₂—, —O—, —N(R²⁶)—, —C(O)—, —CON(R²⁶)—,        —N(R²⁶)C(O)—, —N(R²⁶)CON(R²⁷)—, —N(R²⁶)C(O)O—, —OC(O)N(R²⁶)—,        —N(R²⁶)SO₂—, —SO₂N(R²⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—,        —S(O)₂—, and —N(R²⁶)SO₂N(R²⁷)—, wherein        -   R²⁶ and R²⁷ are independently selected from the group            consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl,            wherein R²⁶ and R²⁷ are optionally substituted 1-4 times            with R^(c), or R²⁶ and R²⁷ are taken together with the atoms            to which they are attached to form a heterocyclic ring of 5            to 7 members containing 0-2 additional heteroatoms            independently selected from oxygen, nitrogen, and sulfur;    -   Q² is selected from the group consisting of: a direct bond,        C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene,    -   G³ is selected from the group consisting of: -arylene,        -cycloalkylene, -heterocyclylene, -heteroarylene, -fused        arylcycloalkylene, -fused cycloalkylarylene, -fused        cycloalkylheteroarylene, -fused heterocyclylarylene, and -fused        heterocyclylheteroarylene, wherein        -   G³ is optionally substituted 1-4 times with substituents            independently selected from R⁸, wherein R⁸ is selected from            R^(b),    -   G⁴ is selected from the group consisting of: -aryl, -cycloalkyl,        -heterocyclyl, -heteroaryl, -fused arylcycloalkyl, -fused        cycloalkylaryl, -fused cycloalkylheteroaryl, -fused        heterocyclylaryl, and -fused heterocyclylheteroaryl, wherein        -   G⁴ is optionally substituted 1-4 times with substituents            independently selected from R⁹, wherein R⁹ is selected from            R^(b),-   Rings B and C are optionally substituted 1-4 times with substituents    independently selected from the group consisting of R^(b);-   R^(a) is selected from the group consisting of:    -   a) -hydrogen,    -   b) —S(O)_(m)R^(d),    -   c) —S(O)₂OR^(d),    -   d) —S(O)_(m)NR^(d)R^(e),    -   e) —C(O)R^(d),    -   f) —CO₂R^(d),    -   g) —C(O)NR^(d)R^(e),    -   h) -haloalkyl,    -   i) -cycloalkyl,    -   j) -heterocyclyl,    -   k) —C₁₋₁₀ alkyl,    -   l) —C₂₋₁₀ alkenyl,    -   m) —C₂₋₁₀ alkynyl,    -   n) -aryl,    -   o) -heteroaryl,    -   p) —C₁₋₁₀ alkylene-aryl,    -   q) —C₂₋₁₀ alkynylene-aryl,    -   r) —C₁₋₁₀ alkylene-heteroaryl,    -   s) —C₂₋₁₀ alkynylene-heteroaryl, and    -   t) —C(R^(f)R^(g))_(n)-aryl,        -   wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl,            heteroaryl, and cycloalkyl groups are optionally substituted            1-4 times with a group independently selected from R^(e);-   R^(b) is selected from the group consisting of:    -   a) -cycloalkyl,    -   b) -cyano,    -   c) —OR^(d),    -   d) —NO₂,    -   e) -halogen,    -   f) —S(O)_(m)R^(d),    -   g) —SR^(d),    -   h) —S(O)₂OR^(d),    -   i) —S(O)_(m)NR^(d)R^(e),    -   j) —NR^(d)R^(e),    -   k) —O(CR^(f)R^(g))_(n)NR^(d)R^(e),    -   l) —C(O)R^(d),    -   m) —CO₂R^(d),    -   n) —OC₂(CR^(f)R^(g))_(n)CONR^(d)R^(e),    -   o) —OC(O)R^(d),    -   p) —C(O)NR^(d)R^(e),    -   q) —NR^(d) C(O)R^(e),    -   r) —OC(O)NR^(d)R^(e),    -   s) —NR^(d) C(O)OR^(e),    -   t) —NR^(d) C(O)NR^(d)R^(e),    -   u) —CF₃,    -   v) —OCF₃,    -   w) -haloalkyl,    -   x) -haloalkoxy,    -   y) —C₁₋₁₀ alkyl,    -   z) —C₂₋₁₀ alkenyl,    -   aa) —C₂₋₁₀ alkynyl,    -   ab) —C₁₋₁₀ alkylene-aryl,    -   ac) —C₁₋₁₀ alkylene-heteroaryl, and    -   ad) -heteroaryl,        -   wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and            cycloalkyl groups are optionally substituted 1-4 times with            a group independently selected from R^(c);-   R^(c) is selected from the group consisting of:    -   a) -halogen,    -   b) -amino,    -   c) -carboxy,    -   d) -cyano,    -   e) —C₁₋₄ alkyl,    -   f) —O—C₁₋₄ alkyl,    -   g) —O—CF₃,    -   h) -cycloalkyl,    -   i) —O-cycloalkyl,    -   j) -aryl,    -   k) —C₁₋₄ alkylene-aryl,    -   l) -hydroxy,    -   m) —CF₃,    -   n) -haloalkyl,    -   o) -haloalkoxy,    -   p) —O-aryl,    -   q) -heteroaryl,    -   r) -heteroarylene-C₁₋₁₀ alkyl,    -   s) -heterocyclyl,    -   t) —CO₂—C₁₋₁₀ alkyl,    -   u) —CO₂—C₁₋₁₀ alkyl-aryl,    -   v) -fused arylcycloalkyl,    -   w) -alkynylene-heteroaryl,    -   x) -alkylene-aryl,    -   y) -alkynylene-aryl,    -   z) -nitro,    -   aa) —N(H)—C(O)—C₁₋₆-alkyl, and    -   bb) —S—C₁₋₆-alkyl,-   R^(d) and R^(e) are independently selected from the group consisting    of: hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl,    —C₁₋₁₀ alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl,    wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,    heterocyclyl groups are optionally substituted with one to four    substituents independently selected from R^(c); or R^(d) and R^(e)    together with the atoms to which they are attached form a    heterocyclic ring of 5 to 7 members containing 0-2 additional    heteroatoms independently selected from oxygen, sulfur and nitrogen    and optionally substituted with 1-3 times with R^(c),-   R^(f) and R^(g) are independently selected from the group consisting    of: hydrogen, C₁₋₁₀ alkyl, cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl,    -carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are    optionally substituted with one to four substituents independently    selected from R^(c); or R^(f) and R^(g) together with the carbon to    which they are attached form a ring of 5 to 7 members containing 0-2    heteroatoms independently selected from oxygen, sulfur and nitrogen    optionally substituted with 1-3 times with R^(c);-   m is an integer from 1 to 2;-   n is an integer from 1 to 10; and-   p is an integer from 0 to 2;    or a pharmaceutically acceptable salt thereof

In a second exemplary embodiment, the present invention relates tocompounds of the first exemplary embodiment, wherein Rings B and C ofFormula (I) contain no further substitutions.

In a third exemplary embodiment, the present invention relates tocompounds of the first or second exemplary embodiments, wherein, when asubstituent is an aryl group, the aryl group is a phenyl group.

In a fourth exemplary embodiment, the present invention relates tocompounds of the first through third exemplary embodiments, wherein,when a substituent is a heteroaryl group, each of the heteroaryl groupsis independently selected from the group consisting of pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, furanyl, pyrrolyl, pyranyl,thiophenyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl,pyrazolyl, indolyl, benzofurany, benzothiophenyl and quinolinyl.

In a fifth exemplary embodiment, the present invention relates tocompounds of the first through fourth exemplary embodiments, wherein,when a substituent is a heterocyclyl group, each of the heterocyclylgroups is independently selected from the group consisting ofpiperdinyl, piperazinyl, morpholinyl, dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dioxolanyl, imidazolidinyl and pyrazolidinyl.

In a sixth exemplary embodiment, the present invention relates tocompounds of the first through fifth exemplary embodiments, wherein R¹is selected from the group consisting of —CO₂H and —CO₂R¹².

In a seventh exemplary embodiment, the present invention relates tocompounds of the first through fifth exemplary embodiments, wherein R¹is —CO₂H.

In an eighth exemplary embodiment, the present invention relates tocompounds of the first through seventh exemplary embodiments, wherein R²is selected from the group consisting of: hydrogen and —C₁₋₁₀ alkyl.

In a ninth exemplary embodiment, the present invention relates tocompounds of the first through seventh exemplary embodiments, wherein R²is hydrogen.

In a tenth exemplary embodiment, the present invention relates tocompounds of the first through ninth exemplary embodiments, wherein p is1.

In an eleventh exemplary embodiment, the present invention relates tocompounds of the first through tenth exemplary embodiments, wherein L¹is a direct bond.

In a twelfth exemplary embodiment, the present invention relates tocompounds of the first through ninth exemplary embodiments, wherein

-   -   p is 1,    -   G¹ is a substituted or unsubstituted phenyl,    -   L¹ is selected from the group consisting of a direct bond, —O—,        and —N(H)C(O)—,        and    -   G² is a phenyl group substituted 1-4 times with substituents        independently selected from R¹¹, and G² is substituted with at        least one substituent selected from the group consisting of:        -   a) —C₁₋₁₀ alkyl,        -   b) -haloalkyl,        -   c) -haloalkoxy,        -   d) —CF₃,        -   e) —OCF₃,        -   f) -halogen,        -   g) —O—R^(d),        -   h) -cyano,        -   i) —C(O)R^(d),        -   j) —NR^(d) R^(e),        -   k) -cycloalkyl, and        -   l) —CO₂R^(d),        -   wherein alkyl and cycloalkyl groups are optionally            substituted 1-4 times with a group independently selected            from R^(c).

In a thirteenth exemplary embodiment, the present invention relates tocompounds of the first through ninth exemplary embodiments, wherein

-   -   p is 1,    -   G¹ is a C₂₋₁₀ alkylene,    -   L¹ is a direct bond, and    -   G² is a substituted or unsubstituted phenyl group.

In a fourteenth exemplary embodiment, the present invention relates tocompounds of the first through ninth exemplary embodiments, wherein p is1,

-   -   G¹ is —C≡C—,    -   L¹ is a direct bond, and    -   G² is a substituted or unsubstituted phenyl group substituted        1-4 times with substituents independently selected from R¹¹, and        G² is substituted with at least one substituent selected from        the group consisting of:    -   a) —C₁₋₁₀ alkyl,    -   b) -haloalkyl,    -   c) -haloalkoxy,    -   d) —CF₃,    -   e) —OCF₃,    -   f) -halogen,    -   g) —O—R^(d),    -   h) -cyano,    -   i) —C(O)R^(d),    -   j) —NR^(d)R^(e),    -   k) -cycloalkyl,    -   l) —CO₂R^(d),        -   wherein the alkyl and cycloalkyl groups are optionally            substituted 1-4 times with a group independently selected            from R^(c).

In a fifteenth exemplary embodiment, the present invention relates tocompounds of the first through ninth exemplary embodiments, wherein

-   -   p is 1,    -   G¹ is a substituted or unsubstituted phenyl,    -   L¹ is a direct bond, and    -   G² is selected from the group consisting of: indole, pyridine,        pyrimidine, quinoline, isoxazole, wherein G² is optionally        substituted or unsubstituted.

In a sixteenth exemplary embodiment, the present invention relates tocompounds of the first through ninth exemplary embodiments, wherein

-   -   p is 1,    -   G¹ is an unsubstituted phenyl,    -   L¹ is a direct bond, and    -   G² is a phenyl, substituted with a cyano group.

In a seventeenth exemplary embodiment, the present invention relates tocompounds of the first through sixteenth exemplary embodiments, whereinR³ is selected from the group consisting of:

-   -   a) —C₁₋₁₀ alkyl,    -   b) -phenyl,    -   c) -thiopheneyl,    -   d) -furanyl,    -   e) -pyridyl,    -   f) —C₁₋₁₀ alkylene-pyridyl,    -   g) —C₁₋₁₀ alkylene-aminothiazolyl,    -   h) —C₁₋₁₀ alkylene-imidazolyl,    -   i) —C₁₋₁₀ alkylene-oxazolyl,    -   j) —C₁₋₁₀ alkylene-thiopheneyl,    -   k) —C₂₋₁₀ alkynylene-phenyl,    -   l) —C₂₋₁₀ alkynlene-thiopheneyl,    -   m) —C₂₋₁₀ alkynylene-pyridyl,    -   n) —C₂₋₁₀ alkynylene-pyrimidinyl,    -   o) —SO₂-phenyl,    -   p) —CO₂—C₁₋₁₀ alkyl,    -   q) —CO₂-cycloalkyl,    -   r) —CO₂-tetrahydrofuranyl,    -   s) —CO₂-tetrahydropyranyl,    -   t) —CO₂—C₁₋₁₀ alkylene-cycloalkyl,    -   u) —CO₂—C₂₋₁₀-alkynyl,    -   v) —CO₂—CH₂—C≡C-phenyl,    -   w) —C(O)—C₁₋₁₀ alkyl,    -   x) —C(O)-phenyl,    -   y) —C(O)-naphthyl,    -   z) —C(O)-cycloalkyl,    -   aa) —C(O)-furanyl,    -   bb) —C(O)-thiopheneyl,    -   cc) —C(O)-isoxazolyl,    -   dd) —C(O)—C₁₋₁₀ alkylene-cycloalkyl,    -   ee) —C(O)—NH—C₁₋₁₀ alkyl,    -   ff) —C(O)—NH-phenyl, and    -   gg) —C(O)—N(cycloalkyl)-C₁₋₁₀ phenyl,    -   wherein the alkyl, alkynyl, cycloalkyl, tetrahydrofuranyl,        tetrahydropyranyl, phenyl, naphthyl, thiopheneyl, furanyl,        pyridyl, pyrimidinyl, thiazolyl, imidazolyl, oxazolyl, and        isoxazolyl groups are optionally substituted 1-4 times with a        group independently selected from R^(c).

In an eighteenth exemplary embodiment, the present invention relates tocompounds of the first through sixteenth exemplary embodiments, whereinR³ is —C₁₋₁₀ alkyl substituted with a phenyl group.

In a nineteenth exemplary embodiment, the present invention relates tocompounds of the first through sixteenth exemplary embodiments, whereinR³ is selected from the group consisting of:

-   -   a) —CO₂-tert-butyl,    -   b) —CO₂-n-hexyl,    -   c) —CO₂-isopropyl,    -   d) —CO₂-(tert-butylcyclohexyl)    -   e) —CO₂-tetrahydrofuran-2-yl,    -   f) —CO₂-tetrahydropyran-4-yl,    -   g) —CO₂—CH₂-cyclopropyl,    -   h) —C(O)NH-(tert-butylphenyl),    -   i) —C(O)-piperidin-2-yl,    -   j) —C(O)—NH-(trifluoromethoxyphenyl),    -   k) —C(O)—NH-(1,1-diphenylmethyl),    -   l) —C(O)-isopropyl,    -   m) —C(O)-phenyl,    -   n) —C(O)-(fluorophenyl),    -   o) —C(O)-(chlorophenyl),    -   p) —C(O)-(cyanophenyl),    -   q) —C(O)-pyridin-2-yl,    -   r) —C(O)-pyrimidin-4-yl,    -   s) —C(O)-furan-2-yl,    -   t) —C(O)-cyclobutyl,    -   u) —C(O)-cyclopentyl,    -   v) —C(O)-cyclohexyl,    -   w) —C(O)-thiophene-2-yl,    -   x) —C(O)-benzyl,    -   y) —C(O)-(fluorobenzyl),    -   z) —C(O)-(chlorobenzyl),    -   aa) —C(O)-(cyanobenzyl),    -   bb) —C(O)-(2,5-dimethyl-oxazol-4-yl),    -   cc) —CH₂-oxazol-2-yl,    -   dd) —CH₂-(1-methylimdiazol-2-yl),    -   ee) —CH₂-pyridin-2-yl,    -   ff) —CH₂-furan-2-yl,    -   gg) —CH₂-thiazol-2-yl,    -   hh) —CH₂—C≡C-pyrimidin-2-yl,    -   ii) —CH₂—C≡C-phenyl,    -   jj) —CH₂-thiophene-2-yl,    -   kk) —(R)-1-(phenyl)-propyl, and    -   ll) —(S)-1-(phenyl)-propyl.

In an twentieth exemplary embodiment, the present invention relates tocompounds of the first through nineteenth exemplary embodiments, whereinR⁴ is selected from the group consisting of: hydrogen, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl,aryl, heteroaryl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl, heterocyclyl groups are optionallysubstituted with one to four substituents independently selected fromR^(c).

In a twenty-first exemplary embodiment, the present invention relates tocompounds of the first through nineteenth exemplary embodiments, whereinR⁴ is selected from the group consisting of:

-   -   a) -hydrogen,    -   b) —C₁₋₆ alkyl, and    -   c) —C(O)—C₁₋₆ alkyl.

In a twenty-second exemplary embodiment, the present invention relatesto compounds of the first through nineteenth exemplary embodiments,wherein R⁴ is —C₁₋₃ alkyl.

In a twenty-third exemplary embodiment, the present invention relates tocompounds of the first through nineteenth exemplary embodiments, whereinR⁴ is hydrogen.

In a twenty-fourth exemplary embodiment, the present invention relatesto compounds of the first through twenty-third exemplary embodiments,wherein R⁵ is -G³-L²-Q²-L³-G⁴, wherein

-   -   L² is selected from the group consisting of: a direct bond,        —CH₂—, —O—, —N(R₂₆)—, —C(O)—, —CON(R₂₆)—, —N(R₂₆)C(O)—,        —N(R₂₆)CON(R₂₇)—, —N(R₂₆)C(O)O—, —OC(O)N(R₂₆)—, —N(R₂₆)SO₂—,        —SO₂N(R₂₆)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)₂—, and        —N(R₂₆)SO₂N(R₂₇)—,        -   wherein R²⁶ and R²⁷ are independently selected from the            group consisting of: hydrogen, -alkyl, -aryl, and            -alkylene-aryl, wherein R²⁶ and R²⁷ are optionally            substituted 1-4 times with R^(c) or R²⁶ and R²⁷ are taken            together with the atoms to which they are attached to form a            heterocyclic ring of 5 to 7 members containing 0-2            additional heteroatoms independently selected from oxygen,            nitrogen, and sulfur;    -   L³ is a direct bond;    -   Q² is selected from the group consisting of: a direct bond,        C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene;    -   G³ is a phenylene group,        -   wherein G³ is optionally substituted 1-4 times with            substituents independently selected from R⁸, wherein R⁸ is            selected from R^(b); and    -   G⁴ is selected from the group consisting of: -aryl, -cycloalkyl,        -heterocyclyl, -heteroaryl, -fused arylcycloalkyl, -fused        cycloalkylaryl, -fused cycloalkylheteroaryl, -fused        heterocyclylaryl, and -fused heterocyclylheteroaryl,        -   wherein G⁴ is optionally substituted 1-4 times with            substituents independently selected from R⁹, wherein R⁹ is            selected from R^(b).

In a twenty-fifth exemplary embodiment, the present invention relates tocompounds of the first through twenty-third exemplary embodiments,wherein R⁵ is -G³-L²-Q²-L³-G⁴, wherein

-   -   L² is selected from the group consisting of: —CH₂—, —O—,        —N(R²⁶)—, and —C(O)—,        -   wherein R²⁶ is selected from the group consisting of:            hydrogen, -alkyl, -aryl, and -alkylene-aryl;    -   L³ is a direct bond;    -   Q² is a C₁₋₁₀ alkylene group;    -   G³ is a phenylene group,        -   wherein G³ is optionally substituted 1-4 times with            substituents independently selected from R⁸, wherein R⁸ is            selected from R^(b); and    -   G⁴ is selected from the group consisting of: cycloalkyl, phenyl,        pyridinyl, benzothiopheneyl, benzothiazolyl, G⁴ is optionally        substituted 1-4 times with substituents independently selected        from R⁹, wherein R⁹ is selected from R^(b).

In a twenty-sixth exemplary embodiment, the present invention relates tocompounds of the first through twenty-third exemplary embodiments,wherein R⁵ is -G³-L²-Q²-L³-G⁴, wherein

-   -   L² is selected from the group consisting of: —CH₂—, —O—,        —N(R²⁶)—, and —C(O)—,        -   wherein R²⁶ is selected from the group consisting of:            hydrogen, -alkyl, -aryl, and -alkylene-aryl;    -   L³ is a direct bond;    -   Q² is selected from the group consisting of: a direct bond and a        C₁₋₁₀ alkylene group;    -   G³ is a phenylene group,        -   wherein G³ is optionally substituted 1-4 times with            substituents independently selected from R⁸, wherein R⁸ is            selected from R^(b); and    -   G⁴ is a phenyl group, wherein G⁴ is substituted 1-4 times with        substituents independently selected from R⁹, wherein R⁹ is        selected from R^(b), and wherein        -   G⁴ is substituted with at least one substituent selected            from the group consisting of:            -   a) —C₁₋₆ alkyl,            -   b) -haloalkyl,            -   c) -halogen,            -   d) -alkoxy,            -   e) -haloalkoxy,            -   f) —CF₃, and            -   g) —O—CF₃.

In a twenty-seventh exemplary embodiment, the present invention relatesto compounds of the first through twenty-third exemplary embodiments,wherein R⁵ is -G³-L²-Q²-L³-G⁴, wherein

-   -   L² is —O—,    -   L³ is a direct bond;    -   Q² is a C₁₋₁₀ alkylene group;    -   G³ is a phenylene group, and    -   G⁴ is a phenyl group, wherein G⁴ is substituted 1-4 times with        substituents independently selected from R⁹, wherein R⁹ is        selected from R^(b), and wherein        -   G⁴ is substituted with at least one substituent selected            from the group consisting of:            -   h) —C₁₋₆ alkyl,            -   i) -haloalkyl,            -   j) -halogen,            -   k) -alkoxy,            -   l) -haloalkoxy,            -   m) —CF₃, and            -   n) —O—CF₃.

In another embodiment of the present invention, the configuration of thecompound of Formula (I) of the first exemplary embodiment is representedby Formula (I-A):

wherein the variables are as defined above,or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the compound of Formula(I) of the first exemplary embodiment is represented by Formula (I-B):

wherein the variables are as defined above,or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the compound of Formula(I) of the first exemplary embodiment is represented by Formula (I-C):

wherein the variables are as defined above,or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the compound of Formula(I) of the first exemplary embodiment is represented by Formula (I-D):

wherein the variables are as defined above,or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the compound of Formula(I) of the first exemplary embodiment is represented by Formula (I-E):

wherein * indicates the presence of a chiral center which may be in theR- or S-configuration and wherein the variables are as defined above,or a pharmaceutically acceptable salt thereof

In another embodiment, the present invention provides a compound ofFormula (II):

wherein

-   R⁴ is selected from R^(a); and-   R⁵ is -G³-L²-Q²-L³-G⁴, wherein    -   L² and L³ are independently selected from the group consisting        of: a direct bond, —CH₂—, —O—, —N(R²⁶)—, —C(O)—, —CON(R²⁶)—,        —N(R²⁶)C(O)—, —N(R²⁶)CON(R²⁷)—, —N(R²⁶)C(O)O—, —OC(O)N(R²⁶)—,        —N(R²⁶)SO₂—, —SO₂N(R²⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—,        —S(O)₂—, and —N(R²⁶)SO₂N(R²⁷)—, wherein        -   R²⁶ and R²⁷ are independently selected from the group            consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl,            wherein R²⁶ and R²⁷ are optionally substituted 1-4 times            with R^(c), or R²⁶ and R²⁷ are taken together with the atoms            to which they are attached to form a heterocyclic ring of 5            to 7 members containing 0-2 additional heteroatoms            independently selected from oxygen, nitrogen, and sulfur;    -   Q² is selected from the group consisting of: a direct bond,        C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene,    -   G³ is selected from the group consisting of: -arylene,        -cycloalkylene, -heterocyclylene, -heteroarylene, -fused        arylcycloalkylene, -fused cycloalkylarylene, -fused        cycloalkylheteroarylene, -fused heterocyclylarylene, and -fused        heterocyclylheteroarylene, wherein        -   G³ is optionally substituted 1-4 times with substituents            independently selected from R⁸, wherein R⁸ is selected from            R^(b),    -   G⁴ is selected from the group consisting of: -aryl, -cycloalkyl,        -heterocyclyl, -heteroaryl, -fused arylcycloalkyl, -fused        cycloalkylaryl, -fused cycloalkylheteroaryl, -fused        heterocyclylaryl, and -fused heterocyclylheteroaryl, wherein        -   G⁴ is optionally substituted 1-4 times with substituents            independently selected from R⁹, wherein R⁹ is selected from            R^(b),-   wherein R^(a) is selected from the group consisting of:    -   a) -hydrogen,    -   b) —S(O)_(m)R^(d),    -   c) —S(O)₂OR^(d),    -   d) —S(O)_(m)NR^(d)R^(e),    -   e) —C(O)R^(d),    -   f) —CO₂R^(d),    -   g) —C(O)NR^(d)R^(e),    -   h) -haloalkyl,    -   i) -cycloalkyl,    -   j) -heterocyclyl,    -   k) —C₁₋₁₀ alkyl,    -   l) —C₂₋₁₀ alkenyl,    -   m) —C₂₋₁₀ alkynyl,    -   n) -aryl,    -   o) -heteroaryl,    -   p) —C₁₋₁₀ alkylene-aryl,    -   q) —C₂₋₁₀ alkynylene-aryl,    -   r) —C₁₋₁₀ alkylene-heteroaryl,    -   s) —C₂₋₁₀ alkynylene-heteroaryl, and    -   t) —C(R^(f)R^(g))_(n)-aryl,        -   wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl,            heteroaryl, and cycloalkyl groups are optionally substituted            1-4 times with a group independently selected from R^(e);-   R^(b) is selected from the group consisting of:    -   a) -cycloalkyl,    -   b) -cyano,    -   c) —OR^(d),    -   d) —NO₂,    -   e) -halogen,    -   f) —S(O)_(m)R^(d),    -   g) —SR^(d),    -   h) —S(O)₂OR^(d),    -   i) —S(O)_(m)NR^(d)R^(e),    -   j) —NR^(d)R^(e),    -   k) —O(CR^(f)R^(g))_(n)NR^(d)R^(e),    -   l) —C(O)R^(d),    -   m) —CO₂R^(d),    -   n) —OC₂(CR^(f)R^(g))—CONR^(d)R^(e),    -   o) —OC(O)R^(d),    -   p) —C(O)NR^(d)R^(e),    -   q) —NR^(d) C(O)R^(e),    -   r) —OC(O)NR^(d)R^(e),    -   s) —NR^(d) C(O)OR^(e),    -   t) —NR^(d) C(O)NR^(d)R^(e),    -   u) —CF₃,    -   v) —OCF₃,    -   w) -haloalkyl,    -   x) -haloalkoxy,    -   y) —C₁₋₁₀ alkyl,    -   z) —C₂₋₁₀ alkenyl,    -   aa) —C₂₋₁₀ alkynyl,    -   ab) —C₁₋₁₀ alkylene-aryl,    -   ac) —C₁₋₁₀ alkylene-heteroaryl, and    -   ad) -heteroaryl,        -   wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and            cycloalkyl groups are optionally substituted 1-4 times with            a group independently selected from R^(c);-   R^(c) is selected from the group consisting of:    -   a) -halogen,    -   b) -amino,    -   c) -carboxy,    -   d) -cyano,    -   e) —C₁₋₄ alkyl,    -   f) —O—C₁₋₄ alkyl,    -   g) —O—CF₃,    -   h) -cycloalkyl,    -   i) —O-cycloalkyl,    -   j) -aryl,    -   k) —C₁₋₄ alkylene-aryl,    -   l) -hydroxy,    -   m) —CF₃,    -   n) -haloalkyl,    -   o) -haloalkoxy,    -   p) —O-aryl,    -   q) -heteroaryl,    -   r) -heteroarylene-C₁₋₁₀ alkyl,    -   s) -heterocyclyl,    -   t) —CO₂—C₁₋₁₀ alkyl,    -   u) —CO₂—C₁₋₁₀ alkyl-aryl,    -   v) -fused arylcycloalkyl,    -   w) -alkynylene-heteroaryl,    -   x) -alkylene-aryl,    -   y) -alkynylene-aryl,    -   z) -nitro,    -   aa) —N(H)—C(O)—C₁₋₆-alkyl, and    -   bb) —S—C₁₋₆-alkyl,-   R^(d) and R^(e) are independently selected from the group consisting    of: hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl,    —C₁₋₁₀ alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl,    wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,    heterocyclyl groups are optionally substituted with one to four    substituents independently selected from R^(c); or R^(d) and R^(e)    together with the atoms to which they are attached form a    heterocyclic ring of 5 to 7 members containing 0-2 additional    heteroatoms independently selected from oxygen, sulfur and nitrogen    and optionally substituted with 1-3 times with R^(c),-   R^(f) and R^(g) are independently selected from the group consisting    of: hydrogen, C₁₋₁₀ alkyl, cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl,    -carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are    optionally substituted with one to four substituents independently    selected from R^(c); or R^(f) and R^(g) together with the carbon to    which they are attached form a ring of 5 to 7 members containing 0-2    heteroatoms independently selected from oxygen, sulfur and nitrogen    optionally substituted with 1-3 times with R^(c);-   m is an integer from 1 to 2;-   n is an integer from 1 to 10; and-   p is an integer from 0 to 2;    or a pharmaceutically acceptable salt thereof

In another embodiment, the present invention provides a compound ofFormula (III):

wherein

-   R³ is selected from R^(a);-   R⁴ is selected from R^(a); and-   R⁵ is -G³-L²-Q²-L³-G⁴, wherein    -   L² and L³ are independently selected from the group consisting        of: a direct bond, —CH₂—, —O—, —N(R²⁶)—, —C(O)—, —CON(R²⁶)—,        —N(R²⁶)C(O)—, —N(R²⁶)CON(R²⁷)—, —N(R²⁶)C(O)O—, —OC(O)N(R²⁶)—,        —N(R²⁶)SO₂—, —SO₂N(R²⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—,        —S(O)₂—, and —N(R²⁶)SO₂N(R²⁷)—, wherein        -   R²⁶ and R²⁷ are independently selected from the group            consisting of: hydrogen, -alkyl, -aryl, and -alkylene-aryl,            wherein R²⁶ and R²⁷ are optionally substituted 1-4 times            with R^(c), or R²⁶ and R²⁷ are taken together with the atoms            to which they are attached to form a heterocyclic ring of 5            to 7 members containing 0-2 additional heteroatoms            independently selected from oxygen, nitrogen, and sulfur;        -   Q² is selected from the group consisting of: a direct bond,            C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene,        -   G³ is selected from the group consisting of: -arylene,            -cycloalkylene, -heterocyclylene, -heteroarylene, -fused            arylcycloalkylene, -fused cycloalkylarylene, -fused            cycloalkylheteroarylene, -fused heterocyclylarylene, and            -fused heterocyclylheteroarylene, wherein            -   G³ is optionally substituted 1-4 times with substituents                independently selected from R⁸, wherein R⁸ is selected                from R^(b),        -   G⁴ is selected from the group consisting of: -aryl,            -cycloalkyl, -heterocyclyl, -heteroaryl, -fused            arylcycloalkyl, -fused cycloalkylaryl, -fused            cycloalkylheteroaryl, -fused heterocyclylaryl, and -fused            heterocyclylheteroaryl, wherein        -   G⁴ is optionally substituted 1-4 times with substituents            independently selected from R⁹, wherein R⁹ is selected from            R^(b),            wherein R^(a) is selected from the group consisting of:    -   a) -hydrogen,    -   b) —S(O)_(m)R^(d),    -   c) —S(O)₂R^(d),    -   d) —S(O)_(m)NR^(d)R^(e),    -   e) —C(O)R^(d),    -   f) —CO₂R^(d),    -   g) —C(O)NR^(d)R^(e),    -   h) -haloalkyl,    -   i) -cycloalkyl,    -   j) -heterocyclyl,    -   k) —C₁₋₁₀ alkyl,    -   l) —C₂₋₁₀ alkenyl,    -   m) —C₂₋₁₀ alkynyl,    -   n) -aryl,    -   o) -heteroaryl,    -   p) —C₁₋₁₀ alkylene-aryl,    -   q) —C₂₋₁₀ alkynylene-aryl,    -   r) —C₁₋₁₀ alkylene-heteroaryl,    -   s) —C₂₋₁₀ alkynylene-heteroaryl,    -   t) —C(R^(f)R^(g))_(n)-aryl,        -   wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl,            heteroaryl, and cycloalkyl groups are optionally substituted            1-4 times with a group independently selected from R^(e);-   R^(b) is selected from the group consisting of:    -   a) -cycloalkyl,    -   b) -cyano,    -   c) —OR^(d),    -   d) —NO₂,    -   e) -halogen,    -   f) —S(O)_(m)R^(d),    -   g) —SR^(d),    -   h) —S(O)₂OR^(d),    -   i) —S(O)_(m)NR^(d)R^(e),    -   j) —NR^(d)R^(e),    -   k) —O(CR^(f)R^(g))_(n)NR^(d)R^(e),    -   l) —C(O)R^(d),    -   m) —CO₂R^(d),    -   n) —OC₂(CR^(f)R^(g))—CONR^(d)R^(e),    -   o) —OC(O)R^(d),    -   p) —C(O)NR^(d)R^(e),    -   q) —NR^(d) C(O)R^(e),    -   r) —OC(O)NR^(d)R^(e),    -   s) —NR^(d) C(O)OR^(e),    -   t) —NR^(d) C(O)NR^(d)R^(e),    -   u) —CF₃,    -   v) —OCF₃,    -   w) -haloalkyl,    -   x) -haloalkoxy,    -   y) —C₁₋₁₀ alkyl,    -   z) —C₂₋₁₀ alkenyl,    -   aa) —C₂₋₁₀ alkynyl,    -   ab) —C₁₋₁₀ alkylene-aryl,    -   ac) —C₁₋₁₀ alkylene-heteroaryl, and    -   ad) -heteroaryl,        -   wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and            cycloalkyl groups are optionally substituted 1-4 times with            a group independently selected from R^(c);-   R^(c) is selected from the group consisting of:    -   a) -halogen,    -   b) -amino,    -   c) -carboxy,    -   d) -cyano,    -   e) —C₁₋₄ alkyl,    -   f) —O—C₁₋₄ alkyl,    -   g) —O—CF₃,    -   h) -cycloalkyl,    -   i) —O-cycloalkyl,    -   j) -aryl,    -   k) —C₁₋₄ alkylene-aryl,    -   l) -hydroxy,    -   m) —CF₃,    -   n) -haloalkyl,    -   o) -haloalkoxy,    -   p) —O-aryl,    -   q) -heteroaryl,    -   r) -heteroarylene-C₁₋₁₀ alkyl,    -   s) -heterocyclyl,    -   t) —CO₂—C₁₋₁₀ alkyl,    -   u) —CO₂—C₁₋₁₀ alkyl-aryl,    -   v) -fused arylcycloalkyl,    -   w) -alkynylene-heteroaryl,    -   x) -alkylene-aryl,    -   y) -alkynylene-aryl,    -   z) -nitro,    -   aa) —N(H)—C(O)—C₁₋₆-alkyl, and    -   bb) —S—C₁₋₆-alkyl,-   R^(d) and R^(e) are independently selected from the group consisting    of: hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl,    —C₁₋₁₀ alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl,    wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl,    heterocyclyl groups are optionally substituted with one to four    substituents independently selected from R^(c); or R^(d) and R^(e)    together with the atoms to which they are attached form a    heterocyclic ring of 5 to 7 members containing 0-2 additional    heteroatoms independently selected from oxygen, sulfur and nitrogen    and optionally substituted with 1-3 times with R^(c),-   R^(f) and R^(g) are independently selected from the group consisting    of: hydrogen, C₁₋₁₀ alkyl, cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl,    -carboxy, and aryl, wherein alkyl, cycloalkyl, and aryl groups are    optionally substituted with one to four substituents independently    selected from R^(c); or R^(f) and R^(g) together with the carbon to    which they are attached form a ring of 5 to 7 members containing 0-2    heteroatoms independently selected from oxygen, sulfur and nitrogen    optionally substituted with 1-3 times with R^(c);-   m is an integer from 1 to 2;-   n is an integer from 1 to 10; and-   p is an integer from 0 to 2;    or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound ofFormula (IV):

wherein R^(NO1) and R^(NO2) are independently selected from NO₂ andhydrogen, provided that one of R^(NO1) and R^(NO2) is hydrogen and theother is NO₂;or a pharmaceutically acceptable salt thereof

Pharmaceutically-acceptable salts of the compounds of the presentinvention, where a basic or acidic group is present in the structure,are also included within the scope of the invention. The term“pharmaceutically acceptable salts” refers to salts of the compounds ofthis invention which are generally prepared by reacting the free basewith a suitable organic or inorganic acid or by reacting the acid with asuitable organic or inorganic base. Representative salts include thefollowing salts: Acetate, Benzenesulfonate, Benzoate, Bicarbonate,Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate, Camsylate,Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate,Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate,Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate,Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide,Trimethylammonium and Valerate. When an acidic substituent is present,such as —COOH, there can be formed the ammonium, morpholinium, sodium,potassium, barium, calcium salt, and the like, for use as the dosageform. The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. When a basic group is present, such as amino or a basicheteroaryl radical, such as pyridyl, an acidic salt, such ashydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate,trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate,methanesulfonate, ethanesulfonate, picrate and the like.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of the invention and these form a furtheraspect of the invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, excipient, diluent, or mixture thereof.

Compounds set forth in the examples below demonstrated utility asmodulators of GLP-1R. Within the context of the present invention, amodulator of GLP-1R may be an agonist, antagonist, partial agonist,partial antagonist, inverse agonist or inverse antagonist. In oneembodiment, compounds of the invention are agonists of GLP-1R. Inanother embodiment, compounds of the invention are antagonists ofGLP-1R.

Within the context of the present invention, a GLP-1R agonist isunderstood to refer to any compound which fully or partially activatesthe human GLP-1 receptor. Within the context of the present invention, apartial GLP-1R agonist is understood to refer to any compound whichincreases the activity of the human GLP-1 receptor but which compared toGLP-1 itself, is not able to effect a full response (E_(max)<100%relative to GLP-1). Within the context of the present invention, a GLP-1antagonist is understood to refer to any compound which decreases theactivity of the human GLP-1 receptor seen after stimulation with GLP-1.Within the context of the present invention, GLP-1 is understood torefer to either or both of the two known native forms GLP-1 (7-36) andGLP-1 (7-37).

In general, embodiments of the present invention useful forpharmaceutical applications may have EC50's as determined by the methodfor determining the ability to stimulate cAMP formation in a cell lineexpressing the cloned GLP-1R, such as the one described below, of lessthan 100 μM. Embodiments of the present invention useful forpharmaceutical applications may have EC50's of less than 10 μM. Forparticular medical indications, EC50's lower than 0.01 μM may be useful.Thus, in another embodiment, compounds of the present invention may haveEC50's in a range of about 0.001 μM to about 10 μM. In anotherembodiment, compounds of the present invention may have EC50's of about0.01 μM to about 3 μM. As stated above, agonist activity may bedetermined by the assay described in the Examples below.

Embodiments of the invention described herein are additionally directedto pharmaceutical compositions and use thereof in methods for modulatingGLP-1R, which methods comprise administering to a subject in need ofmodulation of GLP-1R a compound of Formula (I), defined above.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component can becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the compound to a suitable fine sizeand mixing with an appropriate pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents can also bepresent.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate, or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Examples of suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like.

Lubricants useful in these dosage forms include, for example, sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum, andthe like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture may be prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove. Optional ingredients include binders such ascarboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone,solution retardants such as paraffin, resorption accelerators such as aquaternary salt, and/or absorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture can be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet-forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets.

The compounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anontoxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Depending on the stability of the compound, oral fluids may beadministered by admixing two separate oral fluids, one, for example,which may contain concentrated compound in a stable solution (forexample, at a stable pH), and a second, for example, which may containdiluent, flavoring, buffers and the like. The second oral fluid may notbe stable under the same stability conditions for which the first oralfluid is stable.

Any solvent which is pharmaceutically acceptable and which is able todissolve a compound of the present invention may be used. The solutionmay also contain one or more additional components such as aco-solubilizing agent, which may be the same as a solvent, a tonicityadjustment agent, a stabilizing agent, a preservative, or mixturesthereof. Suitable solvents and co-solubilizing agents may include, butare not limited to, water; sterile water for injection (SWFI);physiological saline; alcohols, such as ethanol, benzyl alcohol and thelike; glycols and polyalcohols, such as propyleneglycol, glycerin andthe like; esters of polyalcohols, such as diacetine, triacetine and thelike; polyglycols and polyethers, such as polyethyleneglycol 400,propyleneglycol methylethers and the like; dioxolanes, such asisopropylidenglycerin and the like; dimethylisosorbide; pyrrolidonederivatives, such as 2-pyrrolidone, N-methyl-2-pyrrolidone,polyvinylpyrrolidone, as a co-solubilizing agent and the like;polyoxyethylenated fatty alcohols; esters of polyoxyethylenated fattyacids; polysorbates, such as Tween™, polyoxyethylene derivatives ofpolypropyleneglycols, such as Pluronics™. Suitable tonicity adjustmentagents may include, but are not limited to, pharmaceutically acceptableinorganic chlorides, such as sodium chloride; dextrose; lactose;mannitol; sorbitol, and the like. Preservatives suitable forphysiological administration may be, for instance, esters ofparahydroxybenzoic acid, for example methyl, ethyl, propyl and butylesters, or mixtures thereof, chlorocresol, and the like. Suitablestabilizing agents include, but are not limited to, monosaccharides suchas galactose and fructose, disaccharides such as lactose,polysaccharides such as dextran, cyclic oligosaccharides such as alpha-,beta-, and gamma-cyclodextrin, aliphatic polyols such as mannitol,sorbitol, and thioglycerol, cyclic polyols such as inositol and organicsolvents such as ethyl alcohol and glycerol. The above mentionedsolvents and co-solubilizing agents, tonicity adjustment agents,stabilizing agents and preservatives can be used alone or as a mixtureof two or more of them in a solution formulation.

For example, a pharmaceutical solution formulation may comprise acompound the present invention, SWFI, and an agent selected from thegroup consisting of sodium chloride solution, namely physiologicalsaline, dextrose, mannitol, or sorbitol, wherein the agent is present inan effective amount. The pH of such a formulation may also be adjustedto improve the storage stability using a pharmaceutically acceptableacid or base.

The compounds of the present invention may be supplied as atwo-component system including a first bottle of concentrated compoundsolution (from about 20 mg/g to about 60 mg/g, typically about 40 mg/g)and a second bottle of sterile diluent at pH 12.

The concentrated compound solution (the first bottle) may bereconstituted with the entire contents of the diluent solution (thesecond bottle) to give a solution, at, for example, 10 mg/ml and havingpH 10.5-11.5.

In one embodiment, a pharmaceutical formulation may include componentsas described in the table below.

Concentrated Diluent for Concentrated Compound Solution CompoundSolution Compound of the present Povidone, USP/NF invention Dibasicsodium phosphate•7H2O, USP/NF Polyethylene glycol 400, Sucralose, USP/NFUSP/NF Banana flavor Polysorbate 80 (Tween 80). D&C yellow #10 USP/NFPurified water, USP/NF Sodium hydroxide to adjust pH

In this embodiment, the concentrated compound solution may bereconstituted as described by first warming the concentrated compoundsolution and the diluent solution to room temperature by placing them atroom temperature for 2 to 3 hours. Then, using a syringe, the entirecontents of the diluent bottle (typically about 7.5 mL) may betransferred into the concentrated compound solution bottle. Aftercomplete addition, the bottle may be swirled and gently shaken to mixthe contents while avoiding foam formation. The reconstituted solution(typically about 10 mg/ml) may be stored at room temperature (15°-30°C., 59°-86° F.) and should be used within about six hours of itsreconstitution. The required volume of reconstituted solution fromvarious bottles may be transferred into a dispensing cup prior toadministration.

Suitable packaging for the pharmaceutical solution formulations may beall approved containers intended for parenteral use, such as plastic andglass containers, ready-to-use syringes and the like. In an embodiment,the container is a sealed glass container, such as a vial or an ampoule.A hermetically sealed glass vial is one example of a typical sealedglass container. According to an embodiment of the present invention,there is provided, in a sealed glass container, a sterile, injectablesolution comprising a compound of the present invention in aphysiologically acceptable solvent, and which has an appropriate pH forstability. Acid salts of the compounds of the present invention may bemore soluble in aqueous solutions than their free base counter parts,but when the acid salts are added to aqueous solutions the pH of thesolution may be too low to be suitable for administration. Thus,solution formulations having a pH above pH 4.5 may be combined prior toadministration with a diluent solution of pH greater than 7 such thatthe pH of the combination formulation administered is pH 4.5 or higher.In one embodiment, the diluent solution comprises a pharmaceuticallyacceptable base such as sodium hydroxide and the pH of the combinedformulation administered is between pH 5.0 and 7.0. One or moreadditional components such as co-solubilizing agents, tonicityadjustment agents, stabilizing agents and preservatives, for instance ofthe kind previously specified, may be added to the solution prior topassing the solution through the sterilizing filter.

The compounds may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinylpyrrolidone (PVP),pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted withpalmitoyl residues. Furthermore, the compounds may be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug; for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base. Pharmaceuticalformulations adapted for topical administrations to the eye include eyedrops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, nebulizers, orinsufflators.

Further, the compositions of the present invention may also be in theform of suppositories for rectal administration of the compounds of theinvention. These compositions can be prepared by mixing the drug with asuitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thus melt inthe rectum to release the drug. Such materials include cocoa butter andpolyethylene glycols, for example. Pharmaceutical formulations adaptedfor rectal administration may be presented as suppositories or asenemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring or coloringagents.

The compounds can be prepared according to the following reactionSchemes (in which variables are as defined before or are defined) usingreadily available starting materials, and reagents. In these reactions,it is also possible to make use of variants which are themselves knownto those of ordinary skill in this art, but are not mentioned in greaterdetail.

Scheme I below describes a method for making key intermediates useful inthe synthesis of compounds of the present invention. Inasmuch, thepresent invention is also directed to certain methods and intermediatecompounds, such as compounds XVIII and XX described below.

In the above Scheme 1 (as well as the below Scheme 2), * represents thepresence of a stereocenter. Each stereocenter may independently be inthe R-configuration, in the S-configuration or be a mixture of R- andS-isomers.

The acid X may be treated with, for example, MeOH in an acidicenvironment, such as in the presence of HCl, to give the methyl esterXI. Treatment of the methyl ester XI with trifluoroacetic acid (TFA) andNaNO₃ gives the nitro methyl ester compound XII and XIII as a mixture ofisomers. The amino group is protected by methods known in the art, forexample, with Boc₂O, and the isomers are separated to give thenitro-boc-methyl ester XIV. This compound may be treated with1-hydroxy-1-R⁵-acetic acid methyl ester under Mitsunobu conditions togive the coupled product XV. Ring closure of the coupled product XV inthe presence of Fe and an organic acid, such as acetic acid (HOAc) givesthe tricyclic compound XVI, which may be contacted with methyl iodide(MeI) in the presence of base, such as K₂CO₃, to give the methylatedtricyclic compound XVII. Finally, deprotection of the amine, forexample, treatment of the boc-protected amine with HCl, givesintermediate compound A, compound XVIII. In one embodiment of thepresent invention, compound XVIII has the following stereospecificstructure:

The group R⁵ in the above Scheme 1 may be as defined as herewithin. Inone embodiment of the present invention, R⁵ is a mono- or di-substitutedbenzyloxy-phenylene group. In another embodiment of the presentinvention, R⁵ is a dichloro-benzyloxy-phenylene group. In still anotherembodiment R⁵ is dichloro-pyridinylmethoxy-phenylene group.

Scheme 2 below, shows the steps to take the intermediate compound A,compound XVIII from above, to intermediate compound B, compound XX shownbelow.

In the above Scheme 2, intermediate compound A, compound XVIII may betreated with R³-Br in the presence of a base, such as NaHCO₃ to give theR³-substituted tricyclic compound XIX. This R³-substituted tricycliccompound XIX may then be treated with base, such as LiOH, to hydrolyzethe methyl ester to give the acid as intermediate compound B, compoundXX.

In the above Scheme 2, R³ may be as defined herewithin. In oneembodiment of the present invention, R³ is 1-phenylpropane. In anotherembodiment of the present invention, R³ may be a substituted carbonylgroup. In still another embodiment of the present invention, R³ may be asubstituted sulfoxide group. In yet another embodiment of the presentinvention, R³ may contain an aryl or heteryl group attached to the ringnitrogen through an alkylene linker.

The acid compound XX, intermediate compound B, may be coupled with anamine of the formula

wherein R, R¹ and R² are as defined herewithin, by treatment witho-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (HBTU) togive a compound of the present invention having the above describedFormula (I).

The above Schemes are further described with reference to the specificexamples and procedures described in the below-identified Examplessection.

Methods of Medical Treatment

In another aspect, the present invention provides a method of activatingGLP-1R comprising the step of administering to a subject in need thereofa therapeutically effective amount of a compound of the presentinvention. The invention further provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of the present invention sufficient toactivate GLP-1R. A GLP-1R activating amount can be an amount thatstimulates cAMP formation in a cell line expressing cloned GLP-1R, orincrease insulin release from isolated human islet cells, or increaseinsulin release in a subject.

In a further aspect, the present invention may provide a methodcomprising administering to a subject a compound of Formula (I) or apharmaceutically acceptable salt thereof. In one embodiment, the presentinvention comprises a method for the activation of GLP-1R comprisingadministering to a subject a compound of Formula (I). In anotherembodiment, the present invention provides a method of treatmentcomprising administering to a subject in need thereof a compound ofFormula (I). In alternate embodiments, the disease, condition, disorderor indication treated using methods of the present invention comprise

-   -   1. disorders wherein activation of the GLP-1 receptor is        beneficial.    -   2. metabolic disorders, wherein activation of the GLP-1 receptor        is beneficial.    -   3. glucose intolerance,    -   4. hyperglycaemia,    -   5. dyslipidemia,    -   6. Type 1 diabetes,    -   7. Type 2 diabetes,    -   8. hypertriglyceridemia,    -   9. syndrome X,    -   10. insulin resistance,    -   11. IGT,    -   12. obesity,    -   13. diabetes as a consequence of obesity,    -   14. diabetic dyslipidemia,    -   15. hyperlipidemia,    -   16. cardiovascular diseases,    -   17. hypertension, and    -   18. complications resulting from or associated with diabetes        including but not limited to neuropathy, retinopathy,        nephropathy, impaired wound healing, and the like.

In another embodiment, the present invention provides a method for theinhibition of intestinal motility comprising administering a compound ofthe present invention or a pharmaceutical composition comprising acompound of the present invention.

In another embodiment, the present invention provides a method forlowering blood glucose in a human comprising administering a compound ofthe present invention or a pharmaceutical composition comprising acompound of the present invention.

In another embodiment, the present invention provides a method fordelaying or preventing the progression from IGT to Type 2 diabetescomprising administering a compound of the present invention or apharmaceutical composition comprising a compound of the presentinvention.

In another embodiment, the present invention provides a method fordelaying or preventing the progression from non-insulin requiring Type 2diabetes to insulin requiring Type 2 diabetes comprising administering acompound of the present invention or a pharmaceutical compositioncomprising a compound of the present invention.

In another embodiment, the present invention provides a method fordelaying or preventing Type 1 diabetes comprising administering acompound of the present invention or a pharmaceutical compositioncomprising a compound of the present invention.

In another embodiment, the present invention provides a method forappetite regulation or treatment of an energy expenditure disorder suchas eating disorders eg bulimia, and other conditions where a weightreduction is required comprising administering a compound of the presentinvention or a pharmaceutical composition comprising a compound of thepresent invention.

In an embodiment, a therapeutically effective amount may beadministered.

In another embodiment, at least one compound of Formula (I) is used,either alone or in combination with one or more known therapeuticagents. In a further embodiment, the present invention provides methodof prevention and/or treatment of a GLP-1R mediated human disease,treatment comprising a) alleviation of one or more symptoms resultingfrom that disorder, to b) an outright cure for that particular disorder;and prevention comprising a) prevention of the onset of the disorder,the method comprising administering to a human in need thereof atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

Factors which may influence what constitutes a therapeutically effectiveamount include, but are not limited to, the size and weight of thesubject, the biodegradability of the therapeutic agent, the activity ofthe therapeutic agent, as well as its bioavailability. Accordingly, inthe context of the therapeutic method of the invention, this method alsois comprised of a method for treating a subject prophylactically, orprior to the onset of diagnosis such disease(s) or disease state(s).

Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s).

The following is a non-exhaustive listing of classes of additionaltherapeutic agents which may be utilized in combination with thecompounds of the present invention: antidiabetics, antiobesity agents,antihypertensive agents, antihypertensive agents, antiatheroscleroticagent, a lipid lowering agent, and agents for the treatment and/orprevention of complications resulting from or associated with diabetesincluding but not limited to neuropathy, retinopathy, nephropathy,impaired wound healing, and the like.

In addition, the compounds of the present invention may also be combinedwith one or more of the following therapeutic agents; infertilityagents, agents for treating polycystic ovary syndrome, agents fortreating growth disorders, agents for treating frailty, agents fortreating arthritis, agents for preventing allograft rejection intransplantation, agents for treating autoimmune diseases, anti-AIDSagents, anti-osteoporosis agents, agents for treating immunomodulatorydiseases, antithrombotic agents, agents for the treatment ofcardiovascular disease, antibiotic agents, anti-psychotic agents, agentsfor treating chronic inflammatory bowel disease or syndrome and/oragents for treating anorexia nervosa.

Antidiabetic

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include

-   -   1. biguanides (e.g., metformin or phenformin),    -   2. glucosidase inhibitors (e.g, acarbose or miglitol),    -   3. insulins (including insulin secretagogues or insulin        sensitizers),    -   4. meglitinides (e.g., repaglinide, and nateglinide),    -   5. sulfonylureas (e.g., glimepiride, glyburide, gliclazide,        chlorpropamide and glipizide),    -   6. biguanide/glyburide combinations (e.g., Glucovance®),    -   7. thiazolidinediones (e.g., troglitazone, rosiglitazone and        pioglitazone),    -   8. PPAR-alpha agonists,    -   9. PPAR-gamma agonists,    -   10. PPAR alpha/gamma dual agonists,    -   11. glycogen phosphorylase inhibitors,    -   12 inhibitors of fatty acid binding protein (aP2),    -   13. DPP-IV inhibitors, and    -   14. SGLT2 inhibitors.

Examples of other suitable glucagon-like peptide-1 compounds that may beused in combination with the compounds of the present invention includeGLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37).

Hypolipidemic/Lipid Lowering Agents

Examples of suitable hypolipidemic/lipid lowering agents that may beused in combination with the compounds of the present invention includeone or more

-   -   1. MTP inhibitors,    -   2. HMG CoA reductase inhibitors,    -   3. squalene synthetase inhibitors,    -   4. fibric acid derivatives,    -   5. lipoxygenase inhibitors,    -   6. cholesterol absorption inhibitors,    -   7. ileal Na⁺/bile acid cotransporter inhibitors,    -   8. upregulators of LDL receptor activity,    -   9. bile acid sequestrants,    -   10. cholesterol ester transfer protein inhibitors and/or    -   11. nicotinic acid and derivatives thereof.

The HMG CoA reductase inhibitors which may be employed in combinationwith one or more compounds of the present invention include

-   -   mevastatin and related compounds,    -   lovastatin (mevinolin) and related compounds,    -   pravastatin and related compounds,    -   simvastatin and related compounds,    -   atorvastatin, fluvastatin, cerivastatin, and atavastatin

Examples of fibric acid derivatives which may be employed in combinationwith one or more compounds of the present invention include fenofibrate,gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate,probucol and the like.

Antihypertensive Agents

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include

-   -   1. beta adrenergic blockers (e.g., alprenolol, atenolol,        timolol, pindolol propranolol and metoprolol),    -   2. calcium channel blockers (L-type and T-type; e.g.        nicardipine, isradipine, nimodipine, diltiazem, felodipine,        verapamil, nifedipine, amlodipine and mybefradil)    -   3. diuretics (e.g., chlorothiazide, hydrochlorothiazide,        flumethiazide, hydroflumethiazide, bendroflumethiazide,        methylchlorothiazide, trichloromethiazide, polythiazide,        benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,        furosemide, musolimine, bumetanide, triamtrenene, amiloride,        spironolactone),    -   4. renin inhibitors,    -   5. ACE inhibitors (e.g., captopril, zofenopril, fosinopril,        enalapril, ceranopril, cilazopril, delapril, pentopril,        quinapril, ramipril, lisinopril, benazepril)    -   6. AT-1 receptor antagonists (e.g., losartan, irbesartan,        valsartan),    -   7. ET receptor antagonists (e.g., sitaxsentan and atrsentan),    -   8. Dual ET/AII antagonist,    -   9. neutral endopeptidase (NEP) inhibitors,    -   10. vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g.,        omapatrilat and gemopatrilat), and    -   11. nitrates.

Antiobesity Agents

Examples of anti-obesity agents that may be used in combination with thecompounds of the present invention include

-   -   1. a NPY receptor antagonist,    -   2. a MCH antagonist,    -   3. a GHSR antagonist,    -   4. a CRH antagonist,    -   5. a beta 3 adrenergic agonist,    -   6. a lipase inhibitor (orlistat),    -   7. a serotonin (and dopamine) reuptake inhibitor (sibutramine,        topiramate or axokine),    -   8. a thyroid receptor beta drug and/or    -   9. an anorectic agent (dexamphetamine, amphetamine, phentermine,        phenylpropanolamine or mazindol).

Antipsychotic Agents

Examples of anti-psychotic agents which may be optionally employed incombination with compounds of the present invention include clozapine,haloperidol, olanzapine and aripiprazole.

It should be understood that any suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances are considered to be within the scope of the presentinvention.

Pharmaceutical Formulations and Dosage

In another aspect, the present invention comprises a pharmaceuticalcomposition comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier, excipient, diluent, or a mixture thereof.

The pharmaceutical compositions containing a compound of the inventionmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous, or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques to form osmotic therapeutic tablets forcontrolled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in an admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conveniently employed as solvent or suspending medium. For thispurpose, any bland fixed oil may be employed using synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the invention. These compositions canbe prepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectaltemperature and will thus melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the invention are contemplated. Forthe purpose of this application, topical applications shall includemouth washes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Generally speaking, a compound of Formula (I) may be administered at adosage level of from about 0.003 to 500 mg/kg of the body weight of thesubject being treated. In an embodiment, a compound of Formula (I) maybe administered at a dosage range between about 0.003 and 200 mg/kg ofbody weight per day. In an embodiment, a compound of Formula (I) may beadministered at a dosage range between about 0.1 to 100 mg/kg of bodyweight per day. The amount of active ingredient that may be combinedwith the carrier materials to produce a single dosage may vary dependingupon the host treated and the particular mode of administration. Forexample, a formulation intended for oral administration to humans maycontain 1 mg to 2 grams of a compound of Formula (I) with an appropriateand convenient amount of carrier material which may vary from about 5 to95 percent of the total composition. Dosage unit forms may generallycontain between from about 5 mg to about 500 mg of active ingredient.This dosage may be individualized by the clinician based on the specificclinical condition of the subject being treated. Thus, it will beunderstood that the specific dosage level for any particular patientwill depend upon a variety of factors including the activity of thespecific compound employed, the age, body weight, general health, sex,diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing therapy.

Although specific embodiments of the present invention are hereinillustrated and described in detail, the invention is not limitedthereto. The above detailed descriptions are provided as exemplary ofthe present invention and should not be construed as constituting anylimitation of the invention. Modifications will be obvious to thoseskilled in the art, and all modifications that do not depart from thespirit of the invention are intended to be included with the scope ofthe appended claims.

EXAMPLES General Procedure A Preparation of Amides Using HBTU

To a stirring solution of a mixture of a carboxylic acid (1.0 eq) HBTU(1.1 eq) and DIEA (2.0 eq) in DMF at room temperature is added an aminoacid methyl ester (1.0 eq), and the mixture is stirred 4-16 h. Aftercompletion of the reaction, sufficient amount of water is added and themixture is extracted with ethyl acetate. The combined organic layer iswashed with 1 N HCl, saturated NaHCO₃ and brine, and then dried oversodium sulfate. The solvent is removed under reduced pressure to affordthe amide, which may be purified by column chromatography on silica gelto afford the desired amide.

General Procedure B Methyl Ester Hydrolysis

To a solution of ester in THF, methanol (4:1 to 1:4), 2 N lithiumhydroxide solution (2-10 eq) is added, and the resulting reactionmixture is stirred at 0° C. or room temperature for 10-120 minutes (ifstarted at 0° C.) and then warmed to room temperature and stirred untilreaction complete. After completion of the reaction, 1N HCl is used toneutralize the base, extracted with ethyl acetate or DCM, the organiclayer was washed with brine, dried over sodium sulfate, and the solventis removed under reduced pressure to afford the product in pure form.

General Procedure C Removal of Tert-Butyl Carbamate

To a stirred solution of the carbamate in DCM is added 4 N HCl indioxane (excess). The reaction is stirred at room temperature untilreaction was complete. Solvents are removed under reduced pressure. Theresidue is triturated with ethyl ether and the precipitated solid isfiltered and dried under vacuum to give desired amine as hydrochloricacid salt.

General Procedure D Reductive Amination

To a solution of a secondary amine (1.0 eq) in dichloroethane ordichloromethane is added an aldehyde (1.0-3 eq), acetic acid (0.25 eq)and sodium triacetoxyborohydride or sodium cyanoborohydride (2-5 eq) andthe mixture is stirred overnight. After completion of the reaction, DCMis added and the organic layer is washed with 10% Na₂CO₃ solution andbrine, and then dried over sodium sulfate. The solvent is removed underreduced pressure to afford the desired amine, which may be purified byflash chromatography.

General Procedure E Preparation of Sulfonamides

To a solution of an amine (1.0 eq) in DCM is added a sulfonyl chloride(1-3 eq), pyridine (1-5 eq) or triethylamine (1-5 eq) and DMAP (cat.amount if required) and the mixture is stirred for 1-16 h. Aftercompletion of the reaction, ethyl acetate is added and the organic layeris washed with 1N HCl, saturated sodium bicarbonate solution and brine,and then dried over sodium sulfate. The solvent is removed under reducedpressure to afford the sulfonamide, which may be purified by flashchromatography. Alternatively, after completion of the reaction, thereaction mixture may be directly purified by flash chromatography.

General Procedure F Preparation of Amides

To a solution of an amine (1.0 eq) in DCM is added an acid chloride (1-3eq), and pyridine (1-5 eq) or triethylamine (1-5 eq) and the mixture isstirred for 1-16 h. After completion of the reaction, ethyl acetate isadded and the organic layer is washed with 1N HCl, saturated sodiumbicarbonate solution and brine, and then dried over sodium sulfate. Thesolvent is removed under reduced pressure to afford the amide, which maybe purified by flash chromatography. Alternatively, after completion ofthe reaction, the reaction mixture may be directly purified by flashchromatography.

General Procedure G Preparation of Alkyl Chloroformates

To a solution of an alcohol (1.0 eq) in DCM is slowly added phosgene(5-6 eq, 20% solution in toluene) at −5° C. stirred for 2-4 h. Aftercompletion of the reaction, the solvents and excess phosgene are removedunder reduced pressure to afford the alkyl chloroformate, which may besubjected to carbamate formation (General procedure H) without furtherpurification.

General Procedure H Preparation of Carbamates

To a solution of an amine (1.0 eq) in DCM is added a chloroformate (1-3eq), and triethylamine (1-5 eq) and the mixture is stirred for 1-16 h.After completion of the reaction, ethyl acetate is added and the organiclayer is washed with 1N HCl, saturated sodium bicarbonate solution andbrine, and then dried over sodium sulfate. The solvent is removed invacuo to afford the carbamate, which may be purified by flashchromatography. Alternatively, after completion of the reaction, thereaction mixture may be directly purified by flash chromatography.

General Procedure I Preparation of Ureas

To a solution of an amine (1.0 eq) in DCM is added a carbamoyl chloride(1-5 eq), and triethylamine (1-5 eq) and the mixture is stirred for 1-16h. After completion of the reaction, ethyl acetate is added and theorganic layer is washed with 1N HCl, saturated sodium bicarbonatesolution and brine, and then dried over sodium sulfate. The solvent isremoved under reduced pressure to afford the urea, which may be purifiedby flash chromatography. Alternatively, after completion of thereaction, the reaction mixture may be directly purified by flashchromatography.

General Procedure J Preparation of Ureas

To a stirred solution of an amine (1.0 eq) in THF or DCM is added DIEA(0-2 eq) followed by alkyl/aryl isocyanate (2 eq). The resultingsolution is stirred at r.t. for 2 h. The reaction mixture is poured intosaturated NaHCO₃ solution and extracted with ethyl acetate. The combinedorganic layer is washed with brine and dried over Na₂SO₄, andconcentrated under reduced pressure, and then may be purified by silicagel flash column chromatography to give the desired urea.

General Procedure K Alkylation of Secondary Amines

To a solution of a secondary amine (1.0 eq) in DMF is added an alkylhalide (1-10 eq), and potassium carbonate or sodium bicarbonate (1-10eq) and the mixture is stirred at room temperature for 2-72 h. Aftercompletion of the reaction, ethyl acetate and water are added. Theorganic layer is washed with water, and then dried over sodium sulfate.The solvent is removed under reduced pressure to afford the desiredtertiary amine, which may be purified by flash chromatography.

General Procedure L Ether Formation Under Mitsunobu Reaction Conditions

To a solution of a phenol (1 eq), an alcohol (1-4 eq) and polymersupported triphenylphosphine (1-4 eq) in anhydrous DCM and/or THF isadded DIAD (1-4 eq) at rt to −5° C. and the reaction mixture is slowlyallowed to warm up to r.t. and stirred for 1-24 h. After completion ofthe reaction the polymer supported triphenylphosphine is removed fromreaction mixture and concentrated under reduced pressure to afforddesired product after flash chromatography on silica gel.

General Procedure M N-Alkylation of Anilides Using Mitsunobu ReactionConditions

To a solution of an anilide (1.0 eq) and alcohol (1-5 eq) in DCM or THFis added polymer supported triphenylphosphine or triphenylphosphine (1-5eq). The mixture is cooled to (−20° C.-0° C.) and DIAD (1-5 eq) isadded. The mixture is stirred at −20° C.-0° C. for 10 min-1 h and thenat room temperature for 1-24 h. After completion of the reaction, thereaction mixture is filtered and the organics concentrated under reducedpressure. The resulting material may be purified by flash chromatographyto give desired product.

General Procedure N Acid Catalyzed Methyl Ester Hydrolysis

To a solution of ester (1 mmol) in dioxane (30 mL), 6 N hydrochloricacid (20 mL) is added, and the resulting reaction mixture is stirred at70° C. for 100 h. After completion, the reaction mixture isconcentrated, neutralized with sodium bicarbonate, extracted with ethylacetate. The organic layer is washed with brine, dried over sodiumsulfate, and the solvent is removed under reduced pressure to afford theproduct.

General Procedure O Preparation of Amides Using EDCI Coupling

To a solution of acid (1 eq) in dichloromethane at room temperature isadded HOBt (1-2 eq) followed by EDCI (1-2 eq), amine (0.9-2 eq) and NMM(2-4 eq. The reaction mixture is stirred for 1 h then the sample istaken and analyzed by LC-MS. After complete conversion, the reactionmixture is diluted with DCM. The mixture is washed with water, with 1 Naqueous solution of HCl, with saturated aqueous solution of NaHCO₃ thenwith brine. The DCM solution is dried over anhydrous Na₂SO₄ andconcentrated by evaporation. The residue may be purified by columnchromatography. Alternatively, the crude mixture was concentrated andpurified by flash chromatography.

General Procedure P Acetamide Deprotection

To a solution of acetamine (1.0 eq) in methanol is added 4N HCl indioxane (10.0 eq.). The mixture is heated at 62° C. for 2-4 h. Themixture is concentrated and the residue is dissolved in DCM and theorganic layer is washed with 10% Na₂CO₃ solution and brine, and driedover sodium sulfate. The solvent is removed under reduced pressure toafford the desired amine, which may be purified by flash chromatography(9:1 to 7:3 hexanes/EtOAc).

General Procedure Q Alkyl Bromide Preparation

Alcohol (1 eq) and triphenylphosphine polystyrene or triphenylphosphine(1-2 eq) are taken in anhydrous dichloromethane and cooled to 0° C.,carbon tetrabromide (1-2 eq) and stirred for 1 h. The reaction isallowed to warm to room temperature and stirred for 2 h. Resin isfiltered and washed with dichloromethane, filtrate is concentrated anddried in vacuum gave corresponding bromide.

Synthesis of Intermediates6-Amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester

Step 1. Esterification

To a suspension of(S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic aciddehydrate (109 mmol) in methanol (150 mL) was added hydrochloric acid(27 mL of 4M solution in dioxane.) at r.t and the reaction mixture wasrefluxed for 4 h. The mixture was concentrated, resuspeneded in 150 mLof MeOH and hydrochloric acid (27 mL of 4M solution in dioxane.) added.The mixture refluxed for 4 h and was concentrated under reducedpressure. The residue was triturated with ether, filtered and washedwith ether to give(S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methylester hydrochloride salt (25.1 g). ¹H NMR (400 MHz, DMSO d6): 10.1 (m,2H), 9.62 (s, 1H), 7.03 (d, 1H), 6.7 (m, 1H), 6.26 (d, 1H), 4.48 (m,1H), 4.21 (s, 2H), 3.77 (s, 3H), 3.17-2.96 (m, 2H).

Step 2. Nitration

To a solution of(S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methylester hydrochloride (102 mmol) in TFA (300 mL) was slowly added sodiumnitrite (102 mmol) at 0° C. The mixture stirred at 0° C. for 3 h. Aftercompletion, excess TFA was removed in vacuo. The residue was taken up inDCM (200 mL) and neutralized with triethylamine (300 mL). The mixturewas concentrated, dissolved in DCM (200 mL) and cooled to 0° C.Triethylamine (306 mmol) and di-tert-butyl dicarbonate (204 mmol) wasadded. After carbamate formation was complete, the reaction mixture wastreated with hydrazine hydrate (30 mL 33% solution in water) to cleavethe carbonate. The reaction mixture was stirred at r.t. for 30 min. Themixture was poured onto 1 N HCl and ethyl acetate. The organic layer waswashed with saturated sodium bicarbonate and brine, dried over sodiumsulfate and concentrated under reduced pressure to give both nitratedregioisomers (6- and 8-Nitro substituted analogs). The residue waspurified with silica gel chromatography using hexanes:ethyl acetate(from 95:5 to 9:1) as an eluent to provide(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester (9.8 g). ¹H NMR (400 MHz, CDCl3):10.45 (d, 1H), 7.9 (s, 1H), 6.95 (d, 1H), 5.19-4.83 (m, 1H), 4.79-4.49(m, 2H), 3.64 (d, 3H), 3.30-3.14 9 m, 2H), 1.50 (d, 9H).

Step 3.(S)-6-Amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester

To a stirred solution of nitro derivative (3.42 g, 10.0 mmol) inmethanol (50 mL) was added Pd—C(342 mg, 10% on activated carbon) and theresultant reaction mixture was subjected to hydrogenation (balloonpressure). The reaction mixture was stirred under hydrogen balloon atr.t. for 16 h. The catalyst was filter off through a pad of celite andthe celite pad was washed with ethyl acetate-methanol mixture (1:1, 25mL). The combined filtrate was concentrated under reduced pressure. Theresulting residue,(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester was used in the next step withoutfurther purification.

Preparation of Substituted Mandelic Acid Esters

To a solution of hydroxy-(4-hydroxy-phenyl)-acetic acid monohydrate (10g) in DMF (50 mL) was added K₂CO₃ (29.7 g) followed by3,4-dichlorobenzyl bromide (16.1 mL). The mixture was stirred at roomtemperature for 3 h. The mixture was poured into water (250 mL) andextracted with EtOAc. The organic layer was washed with water 1N HCl,brine, dried over Na₂SO₄, and concentrated. The resulting solid wastriturated with diethyl ether and filtered to provide[4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid3,4-dichloro-benzyl ester as a white solid (9.4 g). ¹H NMR (400 MHz,DMSO d6): 7.69 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.41 (m, 1H), 7.37(d, 1H), 7.31 (m, 2H), 7.20 (m, 1H), 6.97 (m, 2H), 6.06 (d, 1H), 5.16(d, 1H), 5.1 (m, 4H).

Similar procedure was used to prepare the following mandelic acidderivatives:[4-(5,6-Dichloro-pyridin-3-ylmethoxy)-phenyl]-hydroxy-acetic acid methylester [hydroxy-(4-hydroxy-phenyl)-acetic acid methyl ester was used inplace of hydroxy-(4-hydroxy-phenyl)-acetic acid monohydrate)],[4-(2,5-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid2,5-dichloro-benzyl ester,[4-(2,6-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid2,6-dichloro-benzyl ester,[4-(3-chloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3-chloro-benzylester and [4-(4-chloro-benzyloxy)-phenyl]-hydroxy-acetic acid4-chloro-benzyl ester.

2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride

Step 1. Ester Hydrolysis

2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-acetic acid3,4-dichloro-benzyl ester (9.4 g) was dissolved in 120 mL ofTHF-methanol (4:1) and 2N lithium hydroxide solution (39 mL) added. Theresulting reaction mixture was stirred at room temperature 16 h. Themixture was poured onto 1N HCl and EtOAc and the organic layer waswashed with brine, dried over sodium sulfate, and concentrated. Theresidual oil was taken up in minimal DCM and hexanes added to give asolid. The solid was filtered and washed with hexanes to afford thedesired product [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acidin pure form (6.1 g). ¹H NMR (400 MHz, DMSO d6): 7.69 (d, 1H), 7.63 (d,1H), 7.41 (m, 1H), 7.31 (m, 2H), 6.96 (m, 2H), 5.10 (s, 2H), 4.94 (s,1H).

Step 2. Acid Chloride Preparation

To [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid (2.13 g) wasadded neat SOCl₂ (20 mL) and the solution was refluxed at 70° C. for 3hours and then slowly cooled to room temperature. The excess thionylchloride was removed under reduced pressure. The residue was dissolvedin DCM (3×50 mL) and concentrated under reduced pressure and dried undervacuum to give the product,2-chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride (2.4 g)which was used without further purification.

(7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester

A solution of(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester (3.0 g, 8.5 mmol), resin-boundtriphenylphosphine (17 mmol),[4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid3,4-dichloro-benzyl ester (13.0 mmol) in DCM-THF (1-1, 80 mL) was cooledto 0° C. To this solution was added DIAD (13.0 mmol) and the mixture wasagitated for 10 min at 0° C. and the mixture was slowly allowed to warmup to r.t. and agitated for 16 h. The reaction mixture was filtered,concentrated and the residue passed over a plug of silica-gelhexanes-ethyl acetate (9:1). The resulting residue was dissolved inglacial acetic acid (65 mL) and iron powder (170 mmol) added. Theresulting mixture was heated at 100° C. for 1 h. The mixture was pouredonto water and EtOAc. The organic layer was washed with water, brine,saturated sodium bicarbonate solution and dried over sodium sulfate. Thesolution was concentrated under reduced pressure to give the desiredproduct. This crude product was purified by silica gel columnchromatography using hexanes-ethyl acetate (7:3) to afford(7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (1.6 g). LC-MS (m/z) 614.

(7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (1.6 g) was dissolved inTHF-methanol (4:1, 20 mL), 2 N lithium hydroxide solution (2.5 mL) wasadded, and the resulting reaction mixture was stirred at 0° C. for 3 hwhen an additional equiv of LiOH (2N) was added. The resulting mixturestirred at 0° C. for 3 h. The reaction mixture was neutralized with 1NHCl and extracted with ethyl acetate. The organic layer was washed withbrine, dried over sodium sulfate, and the solvent was removed underreduced pressure to afford3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (1.5 g). LC-MS (m/z) 601.

Similar procedures were used to prepare the following derivatives.(7S)-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester,(7S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester,(7S)-3-[4-(2,5-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester,(7S)-3-[4-(3-chloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester and(7S)-3-[4-(4-chloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester.

Preparation of(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester and(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester

Step 1: Ether Formation by Mitsunobu Reaction

A solution of(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester (1 mmol), triphenylphosphine (1.2mmol) and (R)-[4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acidmethyl ester (1.1 mmol) in DCM was cooled to −5° C. To this solution wasadded DIAD (1.3 mmol) and the mixture was stirred for 45 min at −5° C.and the mixture was slowly allowed to warm up to r.t. and stirred for 1h. After completion of the reaction, the mixture was concentrated andthe residue was purified by silica-gel column chromatography usinghexanes-ethyl acetate (9:1) to afford the desired ether.

Step 2: Cyclization Reaction

To solution of above ether (−1 mmol) in glacial acetic acid (5 mL) wasadded iron powder (5 mmol). The mixture was heated at 80° C. for 30 min.The TLC indicated the complete conversion of starting material. Aftercooling, the solution was diluted with EtOAc (30 mL) and filteredthrough a pad of celite to remove the insoluble solids. The organiclayer was washed with water (2×50 mL), saturated sodium carbonatesolution (1×30 mL), brine (1×30 mL), dried over sodium sulfate. Thesolution was concentrated under reduced pressure to give the desiredproduct as brown oil. This crude product was purified by silica gelcolumn chromatography using hexanes-ethyl acetate (6:4) to afford(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (70%). ¹H NMR (400 MHz, CDCl₃):9.45 (d, 1H), 7.50 (s, 1H), 7.43 (d, 1H), 7.34 (d, 2H), 7.22 (d, 1H),6.92 (d, 2H), 6.93 (d, 1H), 5.59 (s, 2H), 5.12 (m, 1H), 4.98 (s, 2H),4.62 (t, 1H), 4.37 (t, 1H), 4.13 (t, 1H), 3.60 (s, 3H), 3.05 (m, 1H),and 1.46 (d, 9H). LC-MS (m/z) 614.

Similarly(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester was synthesized from (S) mandelicacid derivative. ¹H NMR (400 MHz, CDCl₃): 9.45 (d, 1H), 7.50 (s, 1H),7.43 (d, 1H), 7.34 (d, 2H), 7.22 (d, 1H), 6.92 (d, 2H), 6.93 (d, 1H),5.63 (s, 2H), 5.12 (m, 1H), 4.98 (s, 2H), 4.62 (t, 1H), 4.37 (t, 1H),4.13 (t, 1H), 3.60 (s, 3H), 3.05 (m, 1H), and 1.46 (d, 9H). LC-MS (m/z)614.

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester,(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester,(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester, and(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester

(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-3-nitro-phenyl)-propionicacid methyl ester (16.8 mmol) and(R)-[4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid methyl ester(20.1 mmol) were dissolved in 80 mL of DCM, resin-boundtriphenylphosphine (33.6 mmol) added and the mixture cooled to −20° C.To this solution was added DIAD (25.2 mmol) and the mixture was agitatedfor 30 min at −20° C. The mixture was slowly allowed to warm to r.t. andagitated for 1.5 h. The reaction mixture was filtered and concentrated.The resulting residue was dissolved in glacial acetic acid (60 mL) andheated to 100° C. Iron powder (336 mmol) was added and the resultingmixture heated at 100° C. for 1 h. The mixture was poured onto water andEtOAc. The mixture was brought to ˜pH 7 with sodium carbonate. Theorganic layer was dried over sodium sulfate and concentrated. Theresidue was treated with diethyl ether and the resulting solid filteredand washed with diethyl ether to provide(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionicacid methyl ester (5.7 g). LC-MS (m/z) 502 (M-Boc).

(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionicacid methyl ester (9.5 mmol) was dissolved in 60 mL THF-DCM (1:1) andmethanol (14.2 mmol) and resin-bound triphenylphosphine (14.2 mmol) wasadded. The mixture was cooled to 0° C. and DIAD (14.2 mmol) added. Themixture was agitated for 10 min at 0° C. and the mixture was slowlyallowed to warm up to r.t. and agitated for 16 h. The reaction mixturewas filtered, concentrated and the residue purified over silica-gelhexanes-ethyl acetate (8-2) to afford(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionicacid methyl ester. (4.9 g). ¹H NMR (400 MHz, CDCl3): 7.51 (d, 1H), 7.44(d, 1H), 7.31 (m, 2H), 7.25 (m, 1H), 6.96-6.88 (m, 3H), 6.74 (m, 2H),5.63 (s, 1H), 5.03 (m, 1H), 4.98 (s, 2 h), 4.58 (m, 1 h), 3.70 (s, 3H),3.41 (s, 3H), 3.05 (m, 2H), 1.28 (s, 9H).

(S)-2-tert-Butoxycarbonylamino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionicacid methyl ester (4.9 g) was deprotected according to general procedureC to provide(S)-2-amino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionicacid methyl ester hydrochloride (4.2 g). LC-MS (m/z) 516.

(S)-2-Amino-3-{(S)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl}-propionicacid methyl ester hydrochloride (7.25 mmol) was suspended in 120 mL ofdichloroethane and paraformaldehyde (9.4 mmol) and TFA (20 mL) added.The resulting mixture heated at 70° C. for 5 h. The mixture wasconcentrated and dissolved in DCM. Triethylamine (21.8 mmol) anddi-tert-butyl dicarbonate (10.9 mmol) were added and the mixture stirredat room temperature for 3 h. The mixture was concentrated and purifiedover silica gel (hexanes-EtOAc) to provide(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (4.2 g). NMR (400 MHz, CDCl3):7.51 (d, 1H), 7.44 (d, 1H), 7.30 (m, 2H), 7.23 (m, 1H), 6.90 (m, 2H),6.82-6.71 (m, 2H), 5.62 (s, 1H), 5.16-4.78 (m, 1H), 4.98 (s, 2H),4.68-4.34 (m, 2H), 3.61 (s, 3H), 3.23 (s, 3H), 3.22-3.11 (m, 2H), 1.48(d, 9H).

(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (4.2 g) was deprotected followinggeneral procedure C. The hydrochloride salt was treated with 10% sodiumcarbonate and EtOAc. The aqueous layer was washed with EtOAc and theorganic layers combined. The organic layers were dried over sodiumsulfate and concentrated to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (3.4 g). LC-MS (m/z) 528. NMR (400 MHz, CDCl3): 7.51(d, 1H), 7.44 (d, 1H), 7.29 (m, 2H), 7.23 (m, 1H), 7.68 (m, 2H), 6.69(s, 1H), 6.68 (s, 1H), 5.64 (s, 1H), 4.97 (s, 2H), 4.03 (m, 2H), 3.79(s, 3H), 3.73 (m, 1H), 3.40 (s, 3H), 3.09-2.90 (m, 2H).

Similarly((3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester [NMR (400 MHz, CDCl3): 7.48 (d,1H), 7.43 (d, 1H), 7.28 (m, 2H), 7.21 (m, 1H), 6.88 (m, 2H), 6.80-6.69(m, 2H), 5.64 (s, 1H), 5.18-4.83 (m, 1H), 4.96 (s, 2H), 4.65-4.36 (m,2H), 3.64 (m, 3H), 3.40 (m, 3H), 3.23-3.03 (m, 2H), 1.48 (d, 9H)] and(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester [NMR (400 MHz, CDCl3): 7.49 (d, 1H), 7.43 (d, 1H),7.29 (m, 2H), 7.21 (m, 1H), 6.87 (m, 2H), 6.68 (s, 1H), 6.67 (s, 1H),5.62 (s, 1H), 4.96 (s, 2H), 4.03 (m, 2H), 3.78 (s, 3H), 3.68 (m, 1H),3.39 (s, 3H), 2.94 (m, 2H) were synthesized from (S) mandelic acidderivative.

(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1S-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid and(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1R-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid

(1-Bromo-propyl)-benzene was prepared from 1-phenyl-propan-1-olfollowing general procedure Q and used to prepare the title compound.(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (6.0 g, 11.3 mmol) was reacted with1-bromo-1-phenylpropane (60 mmol) and NaHCO₃ (60 mmol) as described ingeneral procedure K to obtain a 60:40 mixture of methyl esters of titleacids. These compounds were separated by column chromatography on silicagel using hexanes-ethyl acetate. (3:1) to furnish

(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1S-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (2 g) ¹H NMR (400 MHz, CDCl₃): 7.51 (d, 1H), 7.45 (d,1H), 7.35-7.24 (m, 8H), 6.88 (m, 2H), 6.72 (s, 1H), 6.62 (s, 1H), 5.59(s, 1H), 4.9 (s, 2H), 4.13 (m, 2H), 3.87 (m, 1H), 3.62 (m, 1H), 3.54 (s,3H), 3.38 (s, 3H), 3.1-2.81 (m, 2H), 2.3 (m, 1H), 1.8 (m, 1H), 0.53 (t,3H); and

(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1R-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester LC-MS (m/z): 646.

Hydrolysis of(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester using general procedure N provided(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid. LC-MS (m/z): 632.

Similar procedures can be adopted to furnish(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1R-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid.

(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1S-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid and(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1R-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid

(1-Bromo-propyl)-benzene was prepared from 1-phenyl-propan-1-olfollowing general procedure Q and used to prepare the title compound.(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (6.2 g, 12 mmol) was reacted with1-bromo-1-phenylpropane (60 mmol) and NaHCO₃ (60 mmol) as described ingeneral procedure K to obtain a 60:40 mixture of methyl esters of titleacids. These compounds were separated by column chromatography on silicagel using hexanes-ethyl acetate. (3:1) to furnish

(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1S-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (2 3 g)¹H NMR (400 MHz, CDCl₃): 7.51 (d, 1H), 7.45 (d,1H), 7.35-7.24 (m, 8H), 6.88 (m, 2H), 6.72 (s, 1H), 6.62 (s, 1H), 5.64(s, 1H), 4.98 (s, 2H), 4.13 (m, 2H), 3.80 (m, 1H), 3.63 (m, 1H), 3.56(s, 3H), 3.38 (s, 3H), 3.1-2.85 (m, 2H)-2.15 (m, 1H), 1.65 (m, 1H), 0.65(t, 3H); and(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1R-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester LC-MS (m/z): 646.

Hydrolysis of(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester using general procedure N provided(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid. LC-MS (m/z): 632.

Similar procedure can be adopted to furnish(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1R-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid.

(S)-2-Amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methylester-hydrochloride

Step 1. Esterification

To a solution of(5)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (72.6mmol) in DMF (50 mL) was added DIEA (145 mmol) and methyl iodide (363mmol). The reaction mixture stirred at rt for 2.5 h and was poured ontoEtOAc and water. The organic layer was washed with 1 N HCl and 10%sodium carbonate, dried over sodium sulfate and concentrated.(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methylester (25.1 g) was used without further purification. LC-MS (m/z) 359.

Step 2. Suzuki Coupling

To a solution of(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methylester (70.1 mmol) in toluene (250 mL) was added 4-cyanobenzeneboronicacid (105 mmol), Pd(PPh₃)₄ (3.5 mmol), and 1N Na₂CO₃ solution (105 mL).The mixture was heated at reflux for 7 h. After completion of thereaction, the aqueous layer was drained. The organic was washed with 10%Na₂CO₃ and 1 N HCl. The organic was dried over sodium sulfate andconcentrated under reduced pressure to afford the crude product. Theresidue was purified by column chromatography (hexanes-EtOAc) to provide(S)-2-tert-Butoxycarbonylamino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester (18.2 g). LC-MS (m/z) 382.

Step 3. Removal of t-Butyl Carbamate

(S)-2-tert-Butoxycarbonylamino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester (18.1 g) was deprotected following general procedure C toprovide (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methylester-hydrochloride (16.2 g). ¹H NMR (400 MHz, DMSO d6): 8.71 (bs, 3H),7.90 (m, 4H), 7.73 (d, 2H), 7.37 (d, 2H), 4.31 (t, 1H), 3.54 (s, 3H),3.16 (m, 2H).

Similar procedures were used to prepare the following biphenyl alaninederivatives: (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acidmethyl ester; hydrochloride,(S)-2-amino-3-(4′-methoxy-biphenyl-4-yl)-propionic acid methyl ester;hydrochloride, (S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acidmethyl ester; bis-hydrochloride.(S)-2-amino-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester;hydrochloride, (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acidmethyl ester; hydrochloride, and(R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl esterhydrochloride.

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester; hydrochloride (“Intermediate A”)

(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-tert-butyl ester 3-methyl ester (5.1 mmol) was hydrolyzed and coupledwith (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester(5.85 mmol) according to general procedures B and A to provide(S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (2.4 g).(S)-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.1 g) was dissolved in MeOH, Pd/C was added andthe mixture stirred under balloon pressure of hydrogen for 1 h. Mixturewas filtered through celite, washed with MeOH and EtOAc and concentratedto provide(S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.06 g) which was used without furtherpurification.

(S)-6-amino-3-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1.75 mmol) was dissolved in 5 mL EtOAc, 10 mLwater and 15 g sodium bicarbonate added.2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride (1.93mmol) in 5 mL EtOAc was added to the mixture. The resulting mixturestirred at r.t. for 1.5 h. The organic layer was washed with brine,dried over sodium sulfate and concentrated. The resulting residue wasdissolved in 5 mL DMF and potassium carbonate (8.75 mmol) added. Thereaction stirred at r.t. for 3 h and was poured onto ethyl acetate andwater. The organic was dried and concentrated. The residue was purifiedover silica gel (-hexanes-ethyl acetate) to provide(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (931 mg). LC-MS (m/z) 862.

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester hydrochloride (740 mg) was prepared from(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (900 mg) following general procedure C. LC-MS(m/z) 762.

Alternate Procedure to Prepare Intermediate A Step 1: Amide Coupling

To a solution of3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7(S)-dicarboxylicacid 6-tert-butyl ester (2.5 mmol) in DMF was added(S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl esterhydrochloride (2.8 mmol), HBTU (2.8 mmol), and DIEA (5.0 mmol) and themixture was stirred for 3 h. After completion of the reaction,sufficient amount of 1 N HCl was added and the mixture was extractedwith ethyl acetate. The organic layer was washed with 10% sodiumcarbonate and dried over sodium sulfate. The solvent was removed underreduced pressure to afford the amide, which was purified with silica gelchromatography using DCM-ethyl acetate and DCM-acetone to afford thedesired product,(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (807 mg). LC-MS (m/z) 862.

Step 2. Boc-Deprotection

To a stirred solution of this above carbamate (800 mg) in DCM (5 mL) wasadded 4 N HCl in dioxane (15 mL). The reaction was stirred at roomtemperature for 2.5 h. Solvents were removed under reduced pressure toprovide(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester hydrochloride (0.758 g) as hydrochloric acid salt.This product was then used as such for further manipulations. LC-MS(m/z) 762.

Similar procedures may be used to prepare the following intermediates:(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester; hydrochloride,(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(2,5-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester; hydrochloride,(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester; hydrochloride,(S)-2-({(S)-3-[4-(3-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester; hydrochloride, and(S)-2-({(S)-3-[4-(4-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester; hydrochloride.

Preparation of(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester hydrochloride (“Intermediate B”)

(7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (3.0 g, 4.9 mmol) and methanol(9.8 mmol) were dissolved in 60 mL DCM. Resin-bound triphenylphosphine(9.8 mmol) was added and the mixture cooled to 0° C. To this solutionwas added DIAD (9.8 mmol) and the mixture was agitated for 10 min at 0°C. and the mixture was slowly allowed to warm up to r.t. and agitatedfor 4 h. The reaction mixture was filtered, concentrated and the residuepurified over silica-gel hexanes-ethyl acetate (7-3) to afford.(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (3.0 g). LC-MS (m/z) 628.

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (3.0 g) was dissolved inTHF-methanol (4:1, 10 mL), 2 N lithium hydroxide solution (4.8 mL) wasadded, and the resulting reaction mixture was stirred at 0° C. for 5 h.The reaction mixture was neutralized with 1N HCl and extracted withethyl acetate. The organic layer was washed with brine, dried oversodium sulfate, and the solvent was removed under reduced pressure toafford(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (2.9 g). LC-MS (m/z) 614. The Boc group of(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester may be removed to provide thecompound Intermediate C (“Intermediate C”).

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (2.9 g) was coupled to(S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl esterhydrochloride (1.5 g) following general procedure A to provide(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (3.0 g). LC-MS (m/z) 878.

Intermediate B (2.2 g) was prepared from(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (3.0 g) following general procedure C. LC-MS (m/z)776.

(S)-2-Benzyloxycarbonylamino-3-(4-hydroxy-phenyl)-2-methyl-propionicacid methyl ester

To a solution of (S)-2-amino-3-(4-hydroxy-phenyl)-2-methyl-propionicacid (976 mg, 5 mmol) in methanol (50 mL) was added 4N. HCl in dioxane(1.88 mL, 7.5 mmol) and the mixture was refluxed for 4 h. After thecompletion of the esterification, the methanol was evaporated and theresidue was used as such for the next step.

To a suspension of (S)-2-amino-3-(4-hydroxy-phenyl)-2-methyl-propionicacid methyl ester hydrochloride in ethyl acetate (25 mL) was added 1NNaHCO₃ solution (12.5 ml) and the mixture was stirred rapidly at ambienttemperature for the addition of neat benzyl chloroformate (0.859 g, 1.01eq., 5.05 mmol). Following addition, the reaction mixture was stirredfor an additional hour; TLC and LC-MS analysis showed the reaction to becomplete. The mixture was partitioned and the organic phase wasseparated and dried over Na₂SO₄ and concentrated. The crude product wasused directly in the subsequent reaction without purification.

(S)-2-Benzyloxycarbonylamino-2-methyl-3-(4-trifluoro-methanesulfonyloxy-phenyl)-propionicacid methyl ester

To a 0° solution of the crude(S)-2-benzyloxycarbonylamino-3-(4-hydroxy-phenyl)-2-methyl-propionicacid methyl ester (440 mg, 1.28 mmol) in dry DCM (13 mL) was added drypyridine (155 μL) followed by triflic anhydride (259 μL). The reactionmixture was stirred at 0° C. for an additional hour at which pointstarting material was no longer visible by TLC or LC-MS. The mixture wasquenched with of saturated NaHCO₃ solution. The mixture was partitionedand the aqueous phase discarded. The crude product in DCM was washedwith water (30 mL), dried over Na₂SO₄ and concentrated to furnish abrown oil. The crude triflate was used as is without furtherpurification.

(S)-2-Benzyloxycarbonylamino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionicacid methyl ester

In a three necked flask, equipped with reflux condenser, was taken thecrude triflate (609 mg, 1.28 mmol), 4-cyanaophenyl boronic acid (226 mg,1.54 mmol), Na₂CO₃ (350 mg, 2.82 mmol) water (1.41 mL) and totune (5mL). The mixture was stirred and degassed with a stream of nitrogen for45 minutes before adding Pd (PPh₃)₄ (0.01eq. 30 mg). The solution wasdegassing for an additional 20 minutes. The mixture was heated, undernitrogen, to 85° C. for 6 h. The reaction continued until the triflatewas no longer detected by TLC (50% EtOAc/hexanes, PMA char) or by LC-MS.The reaction mixture was cooled to ambient temperature and partitioned.The crude product in toluene concentrated and purified by flashchromatography (7:3 hexane-EtOAc) to get a solid (488 mg). LC-MS (m/z):429. ¹H NMR (400 MHz, CDCl₃): 7.72 (m, 2H), 7.64 (m, 2H), 7.39 (m, 7H),7.06 (d, 2H), 5.52 (bs, 1H) 5.2 (d, 1H), 5.1 (d, 1H), 3.78 (s, 3H), 3.52(m, 2H), 3.23 (d, 2H), 1.68 (s, 3H).

(S)-2-Amino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methylester

The purified cbz-protected amino acid ester (475 mg, 1.11 mmol) wasdissolved in cyclohexene (fw=82.15, p=0.811, 0.23 mL, 2.23 mmol) andethanol (10 mL). To this solution was added Pd/C (48 mg) and the mixturewas degassed for 30 minutes. The mixture was heated at reflux (74-75°C.) for 4-6 hours, at which point starting material was no longerdetected. The reaction mixture was cooled and filtered through celiteand washed with ethyl acetate. The organic layer was concentrated andthe residue was purified by flash column chromatography (gradientelution with 5-50% ethyl acetate in hexanes) afforded the purifiedproduct as a white solid. ¹H NMR (400 MHz, CDCl₃): 7.72 (m, 2H), 7.66(m, 2H), 7.52 (m, 2H), 7.28 (m, 2H), 3.73 (s, 3H), 3.18 (d, 1H), 2.86(d, 1H), 1.7 (bs, 2H), 1.42 (s, 3H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester and(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (6.9 g, 11.5 mmol) was suspended in 30 mL DCMand 1R-2S-5R (−)-menthol (23.0 mmol), EDC (23.0 mmol) and DMAP (cat.)added. The mixture stirred at r.t. for 16 h and the mixture diluted withDCM. The organic layer was washed with 1 N HCl, dried over sodiumsulfate and concentrated. The residue was purified over silica withhexanes-EtOAc gradient (25% EtOAc to 30%) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.0 g) LC-MS (m/z) 738; ¹H NMR (400 MHz, CDCl₃): 8.87 (m, 1H),7.5 (m, 1H), 7.42 (d, 1H), 7.35 (m, 2H), 7.24 (m, 1H), 6.9 (m, 2H), 6.75(m, 1H), 6.6 (s, 1H), 5.56 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (m, 2H),4.3-4.6 (m, 3H), 3.1 (m, 2H), 1.78 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H),1.28 (m, 2H), 0.7-1.0 (m, 9H), 0.4 (m, 3H). and(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester. (3.1 g) LC-MS (m/z) 738; ¹H NMR (400 MHz, CDCl₃): 8.50 (m, 1H),7.5 (d, 1H), 7.43 (d, 1H), 7.37 (m, 2H), 7.21 (m, 1H), 6.9 (m, 2H), 6.76(m, 1H), 6.58 (s, 1H), 5.62 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H),4.6-4.35 (m, 3H), 3.05 (m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H),1.26 (m, 2H), 0.7-1.0 (m, 9H), 0.4 (m, 3H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.0 g) was N-methylated according to general procedure M toprovide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.7 g) LC-MS (m/z) 752.

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.0 g) wasN-methylated according to general procedure M to provide(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.7 g) LC-MS (m/z) 752.

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.7 g) was deprotected using general procedure C to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride (3.1g, LC/MS: m/z 652).

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.9 g) was deprotected using general procedure C to provide(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride (3.2g, LC/MS: m/z 652).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester and(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (2.6 g, 4 mmol) in DMF was treated with (1-bromo-propyl)-benezene(15 mmol) and NaHCO₃ (16 mmol). The mixture was stirred at 40° C. for 48h. The mixture was poured into water, extracted with EtOAc, washed withwater, brine, dried and concentrated. The residue was purified oversilica (EtOAc-hexanes-DCM-TEA, 0.5/5/4.5/0.02) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (401 mg), ¹H NMR(400 MHz, d₆ acetone): 7.7 (d, 1H), 7.6 (d, 1H), 7.46 (d, 1H), 7.33 (m,7H), 6.98 (m, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.65 (s, 1H), 5.13 (s,2H), 4.55 (m, 1H), 4.20 (s, 2H), 3.9 (m, 1H), 3.55 (m, 1H), 3.38 (s,3H), 2.95 (m, 2H), 1.6 (m, 6H), 1.15 (m, 1H), 0.95 (m, 1H) 0.9 (m, 2H),0.8 (m, 4H), 0.7 (d, 3H), 0.65 (m, 6H) and(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (230 mg).

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester and(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (2.6 g, 4 mmol) in DMF was treated with (1-bromo-propyl)-benezene(15 mmol) and NaHCO₃ (16 mmol). The mixture was stirred at 40° C. for 48h. The mixture was poured into water, extracted with EtOAc, washed withwater, brine, dried and concentrated. The residue was purified by flashchromatography (Hexane-EtOAc 4:1) to furnish(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester ¹H NMR (400 MHz,d₆ acetone): 7.68 (s, 1H), 7.58 (d, 1H), 7.45 (d, 1H), 7.33 (m, 7H),6.98 (m, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 5.67 (s, 1H), 5.12 (s, 2H),4.57 (m, 1H), 4.21 (m, 2H), 3.85 (m, 1H), 3.56 (m, 1H), 3.37 (s, 3H),2.95 (m, 2H), 2.9 (3H), 2.2 (m, 1H), 1.6 (m, 6H), 1.15 (m, 1H), 1.0 (m,2H), 0.83 (m, 4H), 0.78 (d, 3H), 0.64 (m, 6H) and(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid 1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (′H NMR (400 MHz,d₆ acetone): 7.67 (d, 1H), 7.59 (d, 1H), 7.46 (d, 1H), 7.33-7.35 (m,7H), 6.91 (m, 2H), 6.88 (s, 1H), 6.54 (s, 1H), 5.62 (s, 1H), 5.09 (s,2H), 4.61 (m, 1H), 4.28 (s, 2H), 3.86-3.74 (m, 3H), 3.55 (d, 1H), 3.38(s, 3H), 3.21-3.0 (m, 3H), 1.6 (m, 6H), 1.4-1.1 (m, 2H), 0.95 (m, 1H)0.9 (m, 2H), 0.8 (m, 4H), 0.79 (d, 3H), 0.62 (m, 6H).

(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid and(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (300 mg) wasdissolved in 10 mL of dry DCM and cooled to 0° C. Boron trichloride (3mL, 1M solution in hexanes) was added and the mixture stirred at 0° C.for 3 hours. The mixture was concentrated and treated withwater/saturated sodium bicarbonate until pH 7. The aqueous mixture wasextracted three times with ethyl acetate-THF (9-1) and organic layercombined. The combined organic layer were dried over sodium sulfate andconcentrated to provide(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (183 mg, LC/MS: m/z 474).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (230 mg) wasdissolved in 10 mL of dry DCM and cooled to 0° C. Boron trichloride (3mL, 1M solution in hexanes) was added and the mixture stirred at 0° C.for 3 hours. Mixture was concentrated and treated with water/saturatedsodium bicarbonate until pH 7. Aqueous mixture was extracted three timeswith ethyl acetate-THF (9-1) and organic layer combined. The combinedorganic layer were dried over sodium sulfate and concentrated to provide(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (153 mg, LC/MS: m/z 474).

(3R,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid and(3R,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid

To a solution of(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.2 mmol) in DCM(3 mL) was added 1N BCl₃ solution in hexane (0.5 mL) at 0° C. and themixture was stirred for 3 h. The mixture was evaporated to dryness andthe residue was quenched with water. The mixture was basified usingsodium bicarbonate solution to pH 7. The residue was extracted withEtOAc and 10% THF. The organic layer was washed and dried to get(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid as a yellow solid (122 mg). This solid was used as is for the nextstep.

(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester was converted to(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (118 mg) using similar procedure as described above and was used asis for the next step.

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (190 mg) was prepared from(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (183 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride following general procedure A. LC-MS (m/z)736.

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (0.259 mmol) was dissolved in 2 mL of DMF and3,4-dichlorobenzyl bromide (1.30 mmol) and potassium carbonate (1.30mmol) were added. The mixture was stirred at room temperature for 6hours and was poured onto ethyl acetate and saturated sodiumbicarbonate. The organic layer was dried over sodium sulfate andconcentrated. The residue was purified over silica (hexanes-ethylacetate-MeOH, 7-3-0.1) to provide(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (96 mg, LC/MS: m/z 895). ¹H NMR (400 MHz, d₆ acetone):7.89-7.77 (m, 5H), 7.56 (m, 2H), 7.49 (m, 2H), 7.34 (m, 1H), 7.30-7.18(m, 7H), 6.97 (s, 1H), 6.84 (m, 2H), 6.78 (m, 2H), 6.71 (s, 1H), 5.65(s, 1H), 4.88 (m, 2H), 4.73 (m, 1H), 3.71 (s, 3H), 3.68 (m, 1H), 3.53(d, 1H), 3.47 (m, 1H), 3.41 (s, 3H), 3.34 (d, 1H), 3.10 (m, 1H), 3.02(m, 1H), 2.83-2.71 (m, 2H), 1.90-1.66 (m, 2H), 0.54 (t, 3H).

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (130 mg) was prepared from(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (153 mg) and (S)-2-mino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride following general procedure A. LC-MS (m/z)736.

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (0.177 mmol) was dissolved in 2 mL of DMF and3,4-dichlorobenzyl bromide (0.885 mmol) and potassium carbonate (0.885mmol) were added. The mixture was stirred at room temperature for 6hours and was poured onto ethyl acetate and saturated sodiumbicarbonate. The organic layer was dried over sodium sulfate andconcentrated. The residue was purified over silica (hexanes-ethylacetate-MeOH, 7-3-0.1) to provide(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester. ¹H NMR (400 MHz, d₆ acetone): 7.77-7.86 (m, 5H), 7.60(d, 1H), 7.54 (m, 3H), 7.37 (dd, 1H), 7.32-7.18 (m, 7H), 6.97 (d, 1H),6.92 (s, 1H), 6.82 (m, 3H), 6.78 (m, 2H), 6.71 (s, 1H), 5.65 (s, 1H),4.95 (m, 2H), 4.66 (m, 1H), 3.76 (m, 2H), 3.70 (s, 3H), 3.58 (m, 2H),3.40 (s, 3H), 3.06 (m, 2H), 3.02 (m, 2H), 2.83-2.72 (m, 2H), 1.96-1.7(m, 2H), 0.54 (t, 3H).

(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (84 mg) was prepared from(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (100 mg) and (S)-2-mino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride following general procedure A.

A similar procedure was used to prepare the following compounds:(S)-3-(4′-chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester,(S)-3-(4′-fluoro-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester, and(S)-2-{[(3R,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester.

(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (15 mg) was dissolved in 1 mL of DMF and3,4-dichlorobenzyl bromide (46 mg) and potassium carbonate (26 mg) wereadded. The mixture was stirred at room temperature for 6 hours and waspoured onto ethyl acetate and saturated sodium bicarbonate. The organiclayer was dried over sodium sulfate and concentrated. The residue waspurified over silica (hexanes-ethyl acetate-MeOH, 6-4-0.1) to provide(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (18 mg, LC/MS: m/z 894). ¹H NMR (400 MHz, d₆ acetone):7.92-7.81 (m, 5H), 7.66 (s, 1H), 7.57 (m, 3H), 7.43 (m, 1H), 7.32-7.21(m, 7H), 7.01-6.94 (m, 5H), 6.66 (s, 1H), 5.60 (s, 1H), 5.1 (s, 2H),4.78 (m, 1H), 3.74 (s, 3H), 3.66 (m, 1H), 3.56 (d, 1H), 3.46 (m, 1H),3.35 (s, 3H), 3.34 (d, 1H), 3.02-2.98 (m, 2H), 2.27 (m, 2H), 1.90-1.66(m, 2H), 0.60 (t, 3H).

(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (68 mg) was prepared from(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (100 mg) and (S)-2-mino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride following general procedure A.

(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester

(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (52 mg) was dissolved in 1 mL of DMF To this solutionwas added 3,4-dichlorobenzyl bromide (33 mg) and potassium carbonate.The mixture was stirred at room temperature for 6 hours and was pouredonto ethyl acetate and saturated sodium bicarbonate. The organic layerwas dried over sodium sulfate and concentrated. The residue was purifiedover silica (hexanes-ethyl acetate-MeOH, 6-4-0.1) to provide(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (16 mg). LC/MS: m/z 894). ¹H NMR (400 MHz, d₆acetone): 7.92-7.81 (m, 5H), 7.66 (s, 1H), 7.57 (m, 3H), 7.43 (m, 1H),7.32-7.21 (m, 7H), 7.01-6.94 (m, 5H), 6.66 (s, 1H), 5.60 (s, 1H), 5.1(s, 2H), 4.78 (m, 1H), 3.74 (s, 3H), 3.66 (m, 1H), 3.56 (d, 1H), 3.46(m, 1H), 3.35 (s, 3H), 3.34 (d, 1H), 3.02-2.98 (m, 2H), 2.27 (m, 2H),1.90-1.66 (m, 2H), 0.60 (t, 3H).

(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester

To a solution of(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (1 mmol) in methanol was added Pd/C (0.2 mmol).The mixture was hydrogenated using balloon for 2-4 h. The mixture waspassed through a pad of celite and the filtrate was evaporated tofurnish(S)-3-(4-Hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester. This ester was converted to(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester using the general procedure A. LC-MS (m/z): 704.

The compounds specifically exemplified below were named based on theirchemical structure using Autonom 2000 (Version 4.1, SP1, Elsevier MDL)plug-in for ISIS Draw and MDL Crossfire Commander AutoNom.

Example 1(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid 4-hydroxy-cyclohexyl ester

Title compound (66 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures H and B. LC-MS (m/z): 890.

Example 2(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid 3-hydroxy-cyclopentyl ester

Title compound (61 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures H and B. LC-MS (m/z): 876.

Example 3(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-4-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (73 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures F and B. LC-MS (m/z): 853.

Example 4(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-3-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (69 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures F and B. LC-MS (m/z): 852.

Example 5(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-((S)-tetrahydro-furan-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (57 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures F and B. LC-MS (m/z): 845.

Example 6(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-((R)-tetrahydro-furan-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (62 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures F and B. LC-MS (m/z): 845.

Example 7(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-phenyl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (44 mg) was prepared from Intermediate A (76 mg, 0.1mmol) following general procedures K and B. LC-MS (m/z): 862.

Example 8(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester

(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester

To a solution of(S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methylester hydrochloride (3.0 g 12.3 mmol) in TFA (40 mL) was slowly addedsodium nitrate (12.3 mmol) at 0° C., then stirred and slowly warmed toroom temperature. After completion excess TFA was removed. The residuewas taken up in DCM (100 mL), neutralized with triethylamine (10 mL) andpassed over a silica plug with ammonia-MeOH/DCM as the eluent. Themixture was concentrated, redissolved in DCM and triethylamine (36.9mmol) and isopropyl chloroformate (29.6 mmol) was added. After carbamateformation was complete, the reaction mixture was treated with hydrazinehydrate (5 mL 33% solution in water) to cleave the carbonate. Thereaction mixture was stirred at r.t. overnight. The mixture wasconcentrated and dissolved in ethyl acetate. The organic was washed with1 N HCl and saturated sodium bicarbonate. The organic layer was driedover sodium sulfate and concentrated under reduced pressure to give bothnitrated regioisomers (6- and 8-Nitro substituted analogs). Theregioisomers(S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester and(S)-7-hydroxy-8-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2 isopropyl ester 3-methyl ester were separated with silica gelchromatography using hexanes:ethyl acetate (from 90:10 to 70:30) as aneluent. LC/MS: m/z 339. ¹H NMR (400 MHz, d₆ DMSO): 10.8 (d, 1H), 7.8 (s,1H), 7.0 (d, 1H), 4.7-5.0 (m, 1H), 4.5-4.7 (m, 1H), 4.4 (m, 1H), 3.5 (d,3H), 3.1 (m, 2H), 1.2 (m, 6H).

(S)-3-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylicacid isopropyl ester

(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (2.4 mmol) was hydrolyzed according togeneral procedure B to provide the acid (0.704 g).(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester (2.16 mmol) was coupled with(S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methylester-hydrochloride (2.38 mmol) according to general procedure A toprovide the amide (1.01 g) LC/MS: m/z 588.

(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester

(S)-3-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylicacid isopropyl ester was reduced and alkylated/cyclized following asimilar procedure described in the synthesis of Intermediate A toprovide(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester (0.037 mg) LC/MS: m/z 848, 850.

(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester (35 mg) was hydrolyzed according to generalprocedure B to provide Title compound (28 mg) LC/MS: m/z 834.

Example 9(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isobutyl ester

Title compound (37 mg) was prepared from(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester; hydrochloride (100 mg) following general procedures Hand B. LC-MS (m/z): 850.

Example 10(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid 2,2-dimethyl-propyl ester

Title compound (34 mg) was prepared from Intermediate A (100 mg)following general procedures H and B. LC-MS (m/z): 862.

Example 11(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tetrahydro-pyran-4-yl ester

Title compound (42 mg) was prepared from Intermediate A (100 mg, 0.13mmol) following general procedures H and B. LC-MS (m/z): 877.

Example 12(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclobutanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (46 mg) was prepared from Intermediate A (100 mg, 0.13mmol) following general procedures F and B. LC-MS (m/z): 832.

Example 13(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-isobutyryl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (40 mg) followinggeneral procedures F and B. LC-MS (m/z): 819.

Example 14(S)-2-({(S)-6-Benzenesulfonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound was prepared from Intermediate A (30 mg) followinggeneral procedures E and B. LC-MS (m/z): 888.

Example 15(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound was prepared from Intermediate A (30 mg) followinggeneral procedures F and B. LC-MS (m/z): 852.

Example 16(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopentanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (30 mg) followinggeneral procedures F and B. LC-MS (m/z): 845.

Example 17(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(piperidine-1-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (30 mg) followinggeneral procedures I and B. LC-MS (m/z): 859.

Example 18(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid cyclopropylmethyl ester

Title compound was prepared from Intermediate A (40 mg) followinggeneral procedures H and B. LC-MS (m/z): 845.

Example 19(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid (R)-(tetrahydro-furan-3-yl) ester

Title compound was prepared from Intermediate A (40 mg) followinggeneral procedures H and B. LC-MS (m/z): 862.

Example 20(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(furan-2-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures F and B. LC-MS (m/z): 842.

Example 21(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3-methyl-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures F and B. LC-MS (m/z): 865.

Example 22(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(4-fluoro-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures F and B. LC-MS (m/z): 870.

Example 23(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(4-methoxy-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures F and B. LC-MS (m/z): 882.

Example 24(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-trifluoromethyl-benzoyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures F and B. LC-MS (m/z): 922.

Example 25(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclohexanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (31 mg) was prepared from Intermediate A (50 mg)following general procedures F and B. LC-MS (m/z): 860.

Example 26(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(naphthalene-1-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (28 mg) was prepared from Intermediate A (50 mg)following general procedures F and B. LC-MS (m/z): 902.

Example 27(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(naphthalene-2-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (28 mg) was prepared from Intermediate A (50 mg)following general procedures F and B. LC-MS (m/z): 904.

Example 28(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(thiophene-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (25 mg) was prepared from Intermediate A (30 mg)following general procedures F and B. LC-MS (m/z): 858.

Example 29(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester

Title compound was prepared from(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (20 mg) following general procedure B. LC-MS(m/z): 850.

Example 30(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-(2-cyclopentyl-acetyl)-3-[-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (20 mg) was prepared from Intermediate A (40 mg)following general procedures F and B. LC-MS (m/z): 860.

Example 31(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(5-methyl-isoxazole-3-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (20 mg) was prepared from Intermediate A (40 mg)following general procedures F and B. LC-MS (m/z): 858.

Example 32(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(thiophene-2-sulfonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (20 mg) was prepared from Intermediate A (40 mg)following general procedures E and B. LC-MS (m/z): 896.

Example 33(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-dimethylcarbamoyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (20 mg) was prepared from(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester; hydrochloride (40 mg) following general procedures Iand B. LC-MS (m/z): 819.

Example 34(S)-2-({(S)-6-Benzyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound was prepared from Intermediate A (40 mg) followinggeneral procedures D and B. LC-MS (m/z): 838.

Example 35(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy-phenyl-2-oxo-6-phenethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (40 mg) followinggeneral procedures D and B. LC-MS (m/z): 852.

Example 36(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(2,4,6-trifluoro-benzoyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures F and B. LC-MS (m/z): 908.

Example 37(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(toluene-2-sulfonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures E and B. LC-MS (m/z): 903.

Example 38(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-methyl-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures D and B. LC-MS (m/z): 852.

Example 39(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures D and B. LC-MS (m/z): 839.

Example 40(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-thiophen-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures D and B. LC-MS (m/z): 844.

Example 41(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-fluoro-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (7 mg) was prepared from Intermediate A (40 mg) followinggeneral procedures D and B. LC-MS (m/z): 856.

Example 42(S)-2-({(S)-6-(2-Chloro-benzyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (7 mg) was prepared from Intermediate A (40 mg) followinggeneral procedures D and B. LC-MS (m/z): 873.

Example 43(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-methoxy-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (11 mg) was prepared from Intermediate A (40 mg)following general procedures D and B. LC-MS (m/z): 868.

Example 44(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(6-methyl-pyridin-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (39.9 mg) followinggeneral procedures D and B. LC-MS (m/z): 853.

Example 45(S)-2-({(S)-6-(6-Bromo-pyridin-2-ylmethyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound was prepared from Intermediate A (39.9 mg) followinggeneral procedures D and B. LC-MS (m/z): 921.

Example 46(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-(5-cyano-6-methylsulfanyl-pyridin-2-ylmethyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (39.9 mg) followinggeneral procedures D and B. LC-MS (m/z): 909.

Example 47(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(1H-imidazol-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (39.9 mg) followinggeneral procedures D and B. LC-MS (m/z): 828.

Example 48(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(1-methyl-1H-imidazol-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures D and B. LC-MS (m/z): 842.

Example 49(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy-phenyl]-2-oxo-6-thiazol-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures D and B. LC-MS (m/z): 846.

Example 50(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures F and B. LC-MS (m/z): 853.

Example 51(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-nitro-benzenesulfonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (30 mg) followinggeneral procedures E and B. LC-MS (m/z): 932.

Example 52(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3-nitro-benzenesulfonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (30 mg) followinggeneral procedures E and B. LC-MS (m/z): 933.

Example 53(S)-2-({(S)-6-(2-Cyano-benzyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound was prepared from Intermediate A (20 mg) followinggeneral procedures D and B. LC-MS (m/z): 863.

Example 54(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopropylmethyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound was prepared from Intermediate A (25 mg) followinggeneral procedures D and B. LC-MS (m/z): 802.

Example 55(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-pyrimidin-2-yl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

2-(3-Bromo-prop-1-ynyl)-pyrimidine was prepared from3-Pyrimidin-2-yl-prop-2-yn-1-ol following general procedure Q and usedto prepare the title compound. Title compound (24 mg) was prepared fromIntermediate A (38 mg, 0.05 mmol) following general procedures K and B.LC-MS (m/z): 866.

Example 56(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-thiophen-3-yl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate A (200 mg) followinggeneral procedures D and B. LC-MS (m/z): 869.

Example 57(S)-2-({(S)-6-Benzoyl-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (16 mg) was prepared from(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (50 mg, 0.05 mmol) following the Procedure C, Fand B. LC-MS (m/z): 853.

Example 58(S)-2-({(S)-6-Benzoyl-3-[4-(2,5-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (20 mg) was prepared from(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(2,5-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (40 mg, 0.05 mmol) following the general procedureC and F and B. LC-MS (m/z): 853.

Example 59(S)-2-({(S)-6-Benzoyl-3-[4-(3-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (17 mg) was prepared from(S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (40 mg, 0.05 mmol) following the general procedureC, F and B. LC-MS (m/z): 822.

Example 60(S)-2-({(S)-6-Benzoyl-3-[4-(4-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (16 mg) was prepared from(S)-3-[4-(4-chloro-benzyloxy)-phenyl]-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (40 mg, 0.05 mmol) following the general procedureC, F and B. LC-MS (m/z): 823.

Example 61(S)-2-({(S)-6-Benzoyl-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester was converted to(S)-2-({(S)-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester hydrochloride following general procedure L. and C.Title compound was prepared from(S)-2-({(S)-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester hydrochloride (0.05 mmol) following the generalprocedure F and B. LC-MS (m/z): 886. Example 62(S)-2-({(S)-6-Benzoyl-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester was converted to(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester hydrochloride following the general procedure L and C.Title compound (9 mg) was prepared from(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester hydrochloride following general procedures F and B.LC-MS (m/z): 882. Example 63(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester

Title compound (6 mg) was prepared from(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (10 mg) following the general procedure B. LC-MS(m/z): 851.

Example 64(S)-2-({(S)-6-Benzoyl-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (12 mg) was prepared from(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-2-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (30 mg) following the general procedure C, F andB. LC-MS (m/z): 855.

Example 65(S)-2-({(S)-6-Benzyl-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (7 mg) was prepared from(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-2-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (15 mg) following general procedures C, D and B.LC-MS (m/z): 839.

Example 66(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-6-(thiophene-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (16 mg) was prepared from(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-2-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (42 mg, 0.05 mmol) following general procedures C,F and B. LC-MS (m/z): 859.

Example 67(S)-2-({(S)-3-[4-(3-Chloro-benzyloxy)-phenyl]-2-oxo-6-thiazol-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (16 mg) was prepared from(S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester (40 mg, 0.05 mmol) following general procedures C,D and B. LC-MS (m/z): 811.

Example 68(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester

(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (2.0 g, LC-MS (m/z) 340) was preparedfrom (S)-7-Hydroxy-6-nitro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylicacid methyl ester (2.0 g) following general procedure H.

(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (2.0 g) was dissolved in MeOH and 200mg Pd/C added. The flask was evacuated and placed under balloon pressureof hydrogen. The reaction stirred at r.t. for 1.5 h and was filteredover a plug of celite. The celite plug was washed with EtOAc and DCM.The filtrates were combined and evaporated to provide(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (1.8 g). LC-MS (m/z) 310.

(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (1.8 g) was dissolved in 10 mL EtOAc,20 mL water and 5.0 g sodium bicarbonate added.2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride in 10 mLof EtOAc was added and the mixture stirred at rt for 1.5 h. The organiclayer was washed with brine, dried and evaporated. The residue wasdissolved in 15 mL DMF and potassium carbonate (4.1 g) added. Themixture stirred at r.t. for 3 h and was poured onto water and EtOAc. Theorganic was washed with 1N HCl, dried and evaporated. The residue waspurified over silica (hexanes-EtOAc-2M ammonia in MeOH) to provide(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester 7-methyl ester (2.0 g). LC-MS (m/z) 600.

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester 7-methyl ester (2.0 g) was hydrolyzed followinggeneral procedure B to provide(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester (1.7 g). LC-MS (m/z) 586.

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester (0.342 mmol) was dissolved in DMF (2 mL) andpotassium carbonate (1.71 mmol) and methyl iodide (3.42 mmol) added.Mixture stirred at room temperature for 30 minutes and heat at 40° C.for 4 hours. Mixture was poured on ethyl acetate and water. Organiclayer was washed with 1 N HCl, dried, and concentrated to provide(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester 7-methyl ester (204 mg, LC/MS: m/z 616).

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester 7-methyl ester (204 mg) was hydrolyzed andcoupled to 2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methylester-hydrochloride according to general procedures A and B to provide(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester (161 mg, LC/MS: m/z 862).

Title compound (96 mg) was prepared from(S)-7-[(S)-2-(4′-Cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester (140 mg) according to general procedure B. LC/MS:m/z 848.

Example 69(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(3-phenyl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

(3-Bromo-prop-1-ynyl)-benzene was prepared from 3-phenyl-prop-2-yn-1-olfollowing general procedure Q and used to prepare the title compound.Title compound (140 mg) was prepared from Intermediate B (150 mg) and3-bromo-prop-1-ynyl benzene following general procedures K and B. LC-MS(m/z): 876.

Example 70(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (42 mg) was prepared from Intermediate B (242 mg)following general procedures D (sodium cyanoborohydydride was used inplace of sodium triacetoxy borohydride) and B. LC-MS (m/z): 882.

Example 71(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-ethyl-benzyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (33 mg) was prepared from Intermediate B (38 mg, 0.05mmol) following general procedures D and B. LC-MS (m/z): 880.

Example 72(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-isopropyl-benzyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (28 mg) was prepared from Intermediate B (38 mg, 0.05mmol) following general procedures D and B. LC-MS (m/z): 894.

Example 73(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy-phenyl]-6-indan-2-yl-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

The indanyl intermediate,(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-6-indan-2-yl-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid, (158 mg) was prepared from Intermediate C (175 mg, 0.3 mmol) and2-indanone (0.6 mmol) following the general procedures D and B. Thisindanyl intermediate was used without further purification.

Title compound (32 mg) was prepared from the indanyl intermediate (63mg, 0.1 mmol) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride (36 mg, 0.12 mmol) following generalprocedures A and B. LC-MS (m/z): 879.

Example 74(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopentyl-3-[4-(3,4-dichloro-benzloxphenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

The cyclopentyl intermediate,(S)-6-Cyclopentyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid, (95 mg) was prepared from Intermediate C (130 mg, 0.25 mmol) andcyclopentanone (0.5 mmol) following the general procedures D and B. Thiscyclopentyl intermediate was used without further purification.

Title compound (13 mg) was prepared from the cyclopentyl intermediate(15 mg, 0.025 mmol) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester hydrochloride (8 mg, 0.025 mmol) following generalprocedures A and B. LC-MS (m/z): 830.

Example 75(S)-3-4′-Cyano-biphenyl-4-yl-2-({(S)-6-cyclobutyl-3-[4-(3,4-dichloro-benzyloxy-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (24 mg) was prepared from Intermediate B (38 mg, 0.05mmol) following general procedures D and B. LC-MS (m/z): 844.

Example 76(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclobutyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (22 mg) was prepared from Intermediate B (38 mg, 0.05mmol) following general procedures D and B. LC-MS (m/z): 816.

Example 77(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-cyclopentylmethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

To a solution of (1-Phenyl-cyclopentyl)-methanol (1.0 g, 5.7 mmol) inDCM (20 mL) was added Dess-Martin Periodine (6.8 mmol, 1.2 eq) andsodium bicarbonate (6.8 mmol, 1.2 eq) at 0° C. The reaction mixturestirred at this temperature for 2 h and allowed to warm up slowly toroom temperature. After completion of the reaction, the mixture waspoured into water (50 mL) and extracted with DCM (50 mL). The organicmixture was then dried over sodium sulfate and concentrated underreduced pressure to give 1-Phenyl-cyclopentanecarbaldehyde (812 mg)which was immediately used to synthesize title compound (14 mg) fromIntermediate B (20 mg, 0.025 mmol) following general procedures D and B.LC-MS (m/z): 923.

Example 78(S)-3-4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy-phenyl]-6-ethyl-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid

Title compound (18 mg) was prepared from Intermediate B (38 mg, 0.05mmol) following general procedures D and B. LC-MS (m/z): 792.

Example 79(S)-2-({(S)-6-(Carboxy-phenyl-methyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid

Title compound (32 mg) was prepared from Intermediate B (38 mg, 0.05mmol) following general procedures K and B. LC-MS (m/z): 895.

Example 80(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-ethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

The 1-phen-ethyl intermediate,(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-ethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid, (44 mg) was prepared from Intermediate C (53 mg, 0.1 mmol) and(1-bromo-ethyl)-benzene (38 mg, 0.2 mmol) following the generalprocedures K and B. This 1-phen-ethyl intermediate was used withoutfurther purification.

Title compound (27 mg) was prepared from the 1-phen-ethyl intermediate(31 mg, 0.05 mmol) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester hydrochloride (16 mg, 0.05 mmol) following generalprocedures A and B. LC-MS (m/z): 865.

Example 81(S)-2-({(S)-6-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid (more polar diastereomer)

(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid methyl ester (760 mg) was reacted with2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (381 mg) followinggeneral procedure E to furnish(S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester (800 mg) as a mixture of diastereomers. Thediastereomers were separated by flash chromatography over silica(DCM:EtOAc 9:1-6:4). The more polar diasteromer (LC-MS m/z 982, 12 mg)was hydrolyzed using the general procedure B to furnish title compound(8 mg, more polar diastereomer). LC-MS (m/z): 967.

Example 82(S)-7-((S)-2-Biphenyl-4-yl-1-carboxy-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester

(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (2.0 g, LC-MS (m/z) 340) was preparedfrom (S)-7-Hydroxy-6-nitro-1,2,3,4-tetrahydro-isoquinoline-3-carboxylicacid methyl ester (2.0 g) following general procedure H.

(S)-7-Hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (2.0 g) was dissolved in MeOH and 200mg Pd/C added. The flask was evacuated and placed under balloon pressureof hydrogen. The reaction stirred at rt for 1.5 h and was filtered overa plug of celite. The celite plug was washed with EtOAc and DCM. Thefiltrates were combined and evaporated to provide(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (1.8 g). LC-MS (m/z) 310.

(S)-6-amino-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid2-isopropyl ester 3-methyl ester (1.8 g) was dissolved in 10 mL EtOAc,20 mL water and 5.0 g sodium bicarbonate added.2-Chloro-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-acetyl chloride in 10 mLof EtOAc was added and the mixture stirred at rt for 1.5 h. The organiclayer was washed with brine, dried and evaporated. The residue wasdissolved in 15 mL DMF and potassium carbonate (4.1 g) added. Themixture stirred at rt for 3 h and was poured onto water and EtOAc. Theorganic was washed with 1N HCl, dried and evaporated. The residue waspurified over silica (hexanes-EtOAc-2M ammonia in MeOH) to provide(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester 7-methyl ester (2.0 g). LC-MS (m/z) 600.

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester 7-methyl ester (2.0 g) was hydrolyzed followinggeneral procedure B to provide(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester (1.7 g). LC-MS (m/z) 586.

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-isopropyl ester (120 mg) was coupled with(S)-2-amino-3-biphenyl-4-yl-propionic acid methyl ester hydrochlorideaccording to general procedure A to provide(S)-7-((S)-2-biphenyl-4-yl-1-methoxycarbonyl-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester (151 mg, LC/MS: m/z 825).

Title compound (71 mg) was prepared from(S)-7-((S)-2-biphenyl-4-yl-1-methoxycarbonyl-ethylcarbamoyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester (101 mg) according to general procedure B. LC/MS:m/z 809.

Example 83(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionicacid

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester hydrochloride (1.8 g, LC/MS: m/z 514) was preparedfrom(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (2.2 g) according to generalprocedure C.

(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (1.6 g, LC/MS: m/z 618) was prepared from(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester hydrochloride (1.8 g) according to general procedure Fexcept no work-up was done. The mixture was evaporated and placeddirectly onto silica.

(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (“Intermediate D”) (1.4 g, LC/MS: m/z 604) was prepared from(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (1.6 g) according to general procedure B.

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionicacid methyl ester (61 m g, LC/MS: m/z 842) was prepared fromIntermediate D (100 mg) and(S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester bishydrochloride according to general procedure A.

Title compound (41 m g) was prepared from(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionicacid methyl ester (50 mg) according to general procedure B. LC/MS: m/z828.

Example 84(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionicacid

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionicacid methyl ester (71 m g, LC/MS: m/z 878) was prepared fromIntermediate D (100 mg) and(S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl esterhydrochloride according to general procedure A.

Title compound (50 m g) was prepared from(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionicacid methyl ester (61 mg) according to general procedure B. LC/MS: m/z862.

Example 85(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionicacid

(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionicacid methyl ester hydrochloride (74 mg, LC/MS: m/z 751) was preparedfrom(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (150 mg) and(S)-2-Amino-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl esterhydrochloride according to general procedures A and C.

(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionicacid methyl ester (16 mg, LC/MS: m/z 842) was prepared from(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionicacid methyl ester hydrochloride (54 mg) according to general procedureD.

Title compound (9 mg) was prepared from Title compound methyl ester (16mg) according to general procedure B. LC/MS: m/z 828.

Example 86(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (28 mg) was prepared from(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (46 mg) using general procedures B. LC-MS (m/z): 881.

Example 87(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (28 mg) was prepared from(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (32 mg) r using general procedures B. LC-MS (m/z):881.

Example 88(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (22 mg) was prepared from(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (25 mg) using general procedures B. LC-MS (m/z): 879.

Example 89(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound (54 mg) was prepared from(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (60 mg) using general procedure B. LC-MS (m/z): 879.

Example 90(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

(S)-3-(4′-chloro,-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (74 mg) was converted to(S)-3-(4′-chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (60 mg) using general procedure K. This ester uponhydrolysis furnished title compound (52 mg) using general procedures B.LC-MS (m/z): 888. Example 91(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid

(S)-2-{[(3R,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester was converted to(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester (64 mg) using general procedure K. This ester uponhydrolysis furnished title compound (58 mg) LCMS (m/z): 884.

Example 92(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid

(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester was converted to(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (70 mg) using general procedure K. This ester uponhydrolysis furnished title compound (64 mg) LCMS (m/z): 872.

Example 93(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCMand 1R-2S-5R (−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.)added. The mixture was stirred at rt for 6 h and the mixture was dilutedwith DCM. The organic layer was washed with water and brine, dried oversodium sulfate and concentrated. The residue purified over silica withhexanes-EtOAc gradient (0% EtOAc to 30%) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (2.4 g, ¹H NMR (400 MHz, CDCl₃): 8.2 (m, 1H), 7.5 (m, 1H), 7.42(d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s,1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1(m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m,9H), 0.4 (m, 3H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester was N-methylated (3.9 g) according to general procedure M toprovide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (4.9 g, not isolated as pure material).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.9 g) was deprotected using general procedure C to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride (3.5g, LC/MS: m/z 652).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.5 g, 5.37 mmol)was dissolved in 10 mL DMF and sodium bicarbonate (21.5 mmol) and(1-Bromo-propyl)-benzene (10.7 mmol) added. The mixture was stirred at50° C. for 20 h and room temperature for 48 hours. The mixture waspoured onto diethyl ether and 10% sodium carbonate. The aqueous layerwas extracted with ether and organic layers combined. The organic layerwas dried over sodium sulfate and concentrated. The residue was purifiedover silica (EtOAc-hexanes-DCM-TEA, 0.5/5/4.5/0.02) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (803 mg, ¹H NMR(400 MHz, d₆ acetone): 7.7 (d, 1H), 7.6 (d, 1H), 7.46 (d, 1H), 7.33 (m,7H), 6.98 (m, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.65 (s, 1H), 5.13 (s,2H), 4.55 (m, 1H), 4.20 (s, 2H), 3.9 (m, 1H), 3.55 (m, 1H), 3.38 (s,3H), 2.95 (m, 2H), 1.6 (m, 6H), 1.15 (m, 1H), 0.95 (m, 1H) 0.9 (m, 2H),0.8 (m, 4H), 0.7 (d, 3H), 0.65 (m, 6H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.80 g) wasdissolved in 20 mL of dry DCM and cooled to 0° C. Boron trichloride (8mL, 1M solution in hexanes) was added and the mixture stirred at 0° C.for 3.5 hours. The mixture was concentrated and treated withwater/saturated sodium bicarbonate until pH 7. The aqueous mixture wasextracted three times with ethyl acetate-THF (9-1) and organic layerscombined. The combined organic layers were dried over sodium sulfate andconcentrated to provide(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (601 mg, LC/MS: m/z 474).

(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (68 mg, LC/MS: m/z 745) was prepared from(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (70 mg) and (S)-2-Amino-3-(4′-chloro-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride using general procedure A.

(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (68 mg, 0.091 mmol) was dissolved in 2 mL of DMF and3,4-dichlorobenzyl bromide (0.46 mmol) and potassium carbonate (0.46mmol) were added. The mixture was stirred at room temperature for 8hours and was poured onto ethyl acetate and 10% sodium carbonate. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified over silica (hexanes-ethylacetate-MeOH, 7-3-0.1) to provide(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (17 mg, LC/MS: m/z 903).

Title compound (8 mg) was prepared from(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (17 mg) according to general procedure B. LC/MS: m/z889.

Example 94(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCMand 1R-2S-5R (−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.)added. The mixture was stirred at r.t. for 6 h and the mixture dilutedwith DCM. The organic layer was washed with water and brine, dried oversodium sulfate and concentrated. The residue purified over silica withhexanes-EtOAc gradient (0% EtOAc to 30%) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (2.4 g, ¹H NMR (400 MHz, CDCl₃): 8.2 (m, 1H), 7.5 (m, 1H), 7.42(d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s,1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1(m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m,9H), 0.4 (m, 3H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester was N-methylated (3.9 g) according to general procedure M toprovide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (4.9 g, not isolated as pure material).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.9 g) was deprotected using general procedure C to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride (3.5g, LC/MS: m/z 652).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.5 g, 5.37 mmol)was dissolved in 10 mL DMF and sodium bicarbonate (21.5 mmol) and(1-Bromo-propyl)-benzene (10.7 mmol) added. The mixture was stirred at50° C. for 20 h and room temperature for 48 hours. The mixture waspoured onto diethyl ether and 10% sodium carbonate. The aqueous layerwas extracted with ether and organic layers combined. The organic layerwas dried over sodium sulfate and concentrated. The residue was purifiedover silica (EtOAc-hexanes-DCM-TEA, 0.5/5/4.5/0.02) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (803 mg, ¹H NMR(400 MHz, d₆ acetone): 7.7 (d, 1H), 7.6 (d, 1H), 7.46 (d, 1H), 7.33 (m,7H), 6.98 (m, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.65 (s, 1H), 5.13 (s,2H), 4.55 (m, 1H), 4.20 (s, 2H), 3.9 (m, 1H), 3.55 (m, 1H), 3.38 (s,3H), 2.95 (m, 2H), 1.6 (m, 6H), 1.15 (m, 1H), 0.95 (m, 1H) 0.9 (m, 2H),0.8 (m, 4H), 0.7 (d, 3H), 0.65 (m, 6H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.80 g) wasdissolved in 20 mL of dry DCM and cooled to 0° C. Boron trichloride (8mL, 1M solution in hexanes) was added and the mixture stirred at 0° C.for 3.5 hours. The mixture was concentrated and treated withwater/saturated sodium bicarbonate until pH 7. The aqueous mixture wasextracted three times with ethyl acetate-THF (9-1) and organic layerscombined. The combined organic layers were dried over sodium sulfate andconcentrated to provide(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (601 mg, LC/MS: m/z 474).

(S)-2-{[(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester (64 mg, LC/MS: m/z 741) was prepared from(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (70 mg) and (S)-2-amino-3-(4′-methoxy-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride using general procedure A.

(S)-2-{[(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester (64 mg, 0.087 mmol) was dissolved in 2 mL of DMF and3,4-dichlorobenzyl bromide (0.43 mmol) and potassium carbonate (0.43mmol) were added. The mixture was stirred at room temperature for 8hours and was poured onto ethyl acetate and 10% sodium carbonate. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified over silica (hexanes-ethylacetate-MeOH, 7-3-0.1) to provide(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester (24 mg, LC/MS: m/z 899).

Title compound (19 mg) was prepared from(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid methyl ester (21 mg) according to general procedure B. LC/MS: m/z886.

Example 95(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCMand 1R-2S-5R (−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.)added. The mixture was stirred at r.t. for 6 h and the mixture wasdiluted with DCM. The organic layer was washed with water and brine,dried over sodium sulfate and concentrated. The residue purified oversilica with hexanes-EtOAc gradient (0% EtOAc to 30%) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (2.4 g, ¹H NMR (400 MHz, CDCl₃): 8.2 (m, 1H), 7.5 (m, 1H), 7.42(d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s,1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1(m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m,9H), 0.4 (m, 3H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester was N-methylated (3.9 g) according to general procedure M toprovide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (4.9 g, not isolated as pure material).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl)ester (3.9 g) was deprotected using general procedure C to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester hydrochloride (3.5g, LC/MS: m/z 652).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (3.5 g, 5.37 mmol)was dissolved in 10 mL DMF and sodium bicarbonate (21.5 mmol) and(1-bromo-propyl)-benzene (10.7 mmol) added. The mixture was stirred at50° C. for 20 h and room temperature for 48 hours. The mixture waspoured onto diethyl ether and 10% sodium carbonate. The aqueous layerwas extracted with ether and organic layers combined. The organic layerwas dried over sodium sulfate and concentrated. The residue was purifiedover silica (EtOAc-hexanes-DCM-TEA, 0.5/5/4.5/0.02) to provide(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (803 mg, ¹H NMR(400 MHz, d₆ acetone): 7.7 (d, 1H), 7.6 (d, 1H), 7.46 (d, 1H), 7.33 (m,7H), 6.98 (m, 2H), 6.87 (s, 1H), 6.77 (s, 1H), 5.65 (s, 1H), 5.13 (s,2H), 4.55 (m, 1H), 4.20 (s, 2H), 3.9 (m, 1H), 3.55 (m, 1H), 3.38 (s,3H), 2.95 (m, 2H), 1.6 (m, 6H), 1.15 (m, 1H), 0.95 (m, 1H) 0.9 (m, 2H),0.8 (m, 4H), 0.7 (d, 3H), 0.65 (m, 6H).

(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (0.80 g) wasdissolved in 20 mL of dry DCM and cooled to 0° C. Boron trichloride (8mL, 1M solution in hexanes) was added and the mixture stirred at 0° C.for 3.5 hours. The mixture was concentrated and treated withwater/saturated sodium bicarbonate until pH 7. The aqueous mixture wasextracted three times with ethyl acetate-THF (9-1) and organic layerscombined. The combined organic layers were dried over sodium sulfate andconcentrated to provide(3S,7S)-3-(4-Hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (601 mg, LC/MS: m/z 474).

(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (57 mg, LC/MS: m/z 729) was prepared from(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (70 mg) and (S)-2-amino-3-(4′-fluoro-biphenyl-4-yl)-propionic acidmethyl ester hydrochloride using general procedure A.

(S)-3-(4′-Fluoro-biphenyl-4-yl)-2-{[(3S,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (27 mg, 0.078 mmol) was dissolved in 2 mL of DMF and3,4-dichlorobenzyl bromide (0.39 mmol) and potassium carbonate (0.39mmol) were added. The mixture was stirred at room temperature for 8hours and was poured onto ethyl acetate and 10% sodium carbonate. Theorganic layer was washed with brine, dried over sodium sulfate andconcentrated. The residue was purified over silica (hexanes-ethylacetate-MeOH, 7-3-0.1) to provide(S)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (21 mg, LC/MS: m/z 889).

Title compound (20 mg) was prepared from(S)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid methyl ester (24 mg) according to general procedure B. LC/MS: m/z873.

Example 96(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3,5-dimethyl-isoxazole-4-sulfonyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

Title compound was prepared from Intermediate B following generalprocedures E and B. LC-MS (m/z): 921.

Example 97(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionicacid

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (31.6 mg) was coupled with(S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methylester (14.7 mg) following general procedure 0 to provide(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionicacid methyl ester (LC-MS (m/z): 909). Title compound was prepared from(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionicacid methyl ester (25 mg) following general procedure B. LC-MS (m/z):893.

Example 98(R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid was coupled to (R)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester following general procedure 0 to provide(R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester. Title compound was prepared from(R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid methyl ester (267 mg) following general procedure B. LC-MS (m/z):880.

Example 99(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-[4-(pyridin-4-yloxy)-phenyl]-propionicacid

(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acid (29.1mmol) was dissolved in 20 mL of DMF and DIEA (58.2 mmol) and methyliodide (146 mmol) added. The reaction mixture stirred at rt for 2 h andwas poured onto EtOAc and 1 N HCl. The organic layer was washed with 1 NHCl and 10% sodium carbonate, dried over sodium sulfate andconcentrated.(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acidmethyl ester (7.8 g) was used without further purification. LC-MS (m/z)297.

(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionic acidmethyl ester (8.46 mmol), 4-pyridyl boronic acid (29.6 mmol), Cu(OAc)₂(16.9 mmol), and molecular sieves were suspended in 25 mL of DCM.Triethylamine (59.2 mmol) was added and the mixture stirred at rt for 10h. The mixture was diluted with ethyl acetate and washed with 10% sodiumcarbonate (6×). The organic layer was dried and concentrated underreduced pressure. The residue was purified over silica gel(hexanes-EtOAc) to provide(S)-2-tert-Butoxycarbonylamino-3-[4-(pyridin-4-yloxy)-phenyl]-propionicacid methyl ester (653 mg). LC-MS (m/z) 374.

(S)-2-Amino-3-[4-(pyridin-4-yloxy)-phenyl]-propionic acid methyl esterbis hydrochloride (543 mg) was prepared from(S)-2-tert-Butoxycarbonylamino-3-[4-(pyridin-4-yloxy)-phenyl]-propionicacid methyl ester (650 mg) following general procedure C. LC-MS (m/z)274.

(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester hydrochloride (1.8 g) was prepared from(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester (2.2 g) following generalprocedure C. LC-MS (m/z) 514.

(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (1.6 g) was prepared from(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester hydrochloride (1.8 g) following general procedure F.LC-MS (m/z) 618.

(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid was prepared (1.4 g) from(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid methyl ester (1.6 g) following general procedure B. LC-MS (m/z)604.

(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-[4-(pyridin-4-yloxy)-phenyl]-propionicacid methyl ester (57 mg) was prepared from(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylicacid (100 mg) and (S)-2-Amino-3-[4-(pyridin-4-yloxy)-phenyl]-propionicacid methyl ester bis hydrochloride (63 mg) following general procedureA. LC-MS (m/z) 858.

Title compound (31 mg) was prepared from Title compound methyl ester (50mg) following general procedure B. LC-MS (m/z) 844.

Example 100(S)-2-({(S)-6-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid (Less polar diastereomer)

(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester 7-methyl ester was hydrolyzed as described ingeneral procedure B to furnish(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylicacid 6-tert-butyl ester as a mixture of diastereomers (1:1) at themorpholino center. This mixture of acids was converted to(S)-7-[(S)-2-(4′-cyano-biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester using the general procedure 0. This intermediatewas further converted to(S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester as a mixture of diastereomeres following the generalprocedure C and E. This sulfonamide was deacylated using the generalprocedure P to furnish(S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester as a mixture of diastereomeres. The diasteromers wereseparated by flash column chromatography (DCM: EtOAc, 9:1-7:3)

The less polar diasteromer (LC-MS m/z 953, 16 mg) upon hydrolysis usingthe general procedure B furnished title compound (less polardiastereomer, 12 mg). LC-MS (m/z): 937.

Example 101(S)-2-({(S)-6-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid (more polar diastereomer)

(S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester (more polar diastereomer, LC-MS m/z 955, 10 mg) washydrolyzed using the general procedure B furnished title compound (morepolar diastereomer 8 mg). LC-MS (m/z) 937.

Example 102(S)-2-({(S)-6-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid (more polar diastereomer)

(S)-2-({(S)-6-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester (more polar diastereomer, 100 mg) was converted to(S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester (LC-MS m/z 941) following the general procedure P.This ester on hydrolysis using general procedure B furnished titlecompound (more polar diastereomer, 70 mg). LC-MS (m/z): 923.

Example 103(S)-2-({(S)-6-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid (less polar diastereomer)

(S)-2-({(S)-6-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester (less polar diastereomer, 100 mg) was converted to(S)-2-({(S)-6-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid methyl ester (LC-MS m/z 940) following the general procedure P.This ester on hydrolysis using general procedure B furnished titlecompound (less polar diastereomer, 72 mg). LC-MS (m/z): 923.

Example 104 Receptor Binding Assay

The affinity of compounds for GLP-1 receptor were studied in an[¹²⁵I]GLP-1(aa 7-36) equilibrium radioligand binding assay. Membranesfrom HEK-293 or CHO cells expressing the human GLP-1 receptor were usedin the GLP-1 receptor binding assay. Reactions were carried out in96-well plates. Compound was diluted in 20% DMSO/water. The final assayconcentration ranging from 0.1 nM to 100 uM in 2% final DMSOconcentration was used. The final binding assay conditions were 25 mMTris-HCL, pH 7.4 buffer containing 10 mM MgCl₂, 1 mM DTT, 0.1 mM EDTA,0.1 mM EGTA, 0.1% BSA, 1-10 ug membrane, 20-200 pM [¹²⁵I]GLP-1 aa (7-36)(SA=2200 Ci/mmoL, (Perkin Elmer part no. NEX308), and compound in finalDMSO concentration of 2% (final assay volume of 100 uL). Positivecontrol wells (C+) lacked compound, and negative control wells (C−)lacked compound and contained cold excess GLP-1 (1 μM). Non-specificbinding (NSB) was determined for each compound concentration by additionof cold excess GLP-1 (1 μM). The reaction was carried out at room tempfor 120 min. Membrane containing bound an [¹²⁵I]GLP-1(aa 7-36) ligandwas isolated following filtration onto Unifilter-96 GF/C filter plates(PerkinElmer part no. 6005177) using a cell harvester instrument. Plateswere washed 5 times with cold 25 mM Tris-HCL, pH 7.5 containing 0.05%bovine serum albumin (BSA). Following filtration, 50 uL of Microscint PS(Packard part no. 6013631) was added, plates were sealed with TopSeal-Aadhesive seals (Packard part no. 6005185). ¹²⁵I isotope bound to theUnifilter-96 GF/C plates was counted using a TopCount instrument(Packard).

Receptor binding data typically ranged from about 40% to about 100%binding vs [¹²⁵I]GLP-1. For example, the compound of Example 15exhibited 68% binding, the compound of Example 39 exhibited 60% binding,the compound of Example 88 exhibited 60% binding, the compound ofexample 89 exhibited 44% binding, and the compound of Example 95exhibited 65% binding.

Data Analysis

Percent inhibition of [¹²⁵I] GLP-1 (aa 7-36) binding was calculatedaccording to the equation100×1-{(Sample_(cpm)−NSB_(cpm))/C+_(cpm)−C−_(cpm))}. Percent inhibitionof [¹²⁵I]GLP-1 binding (Y) vs compound concentration (X) data weregenerated. The IC₅₀ values were calculated by fitting the data usingparameters for a sigmoidal dose response, variable slope nonlinearregression (GraphPAD Prizm, San Diego, Calif.) according to theequation: Y=Bottom+(Top-Bottom)/(1+10̂((Log EC50-X)*HillSlope)) wherein,X is the logarithm of concentration and Y is the response, and Y startsat Bottom and goes to Top with a sigmoid shape. This is identical to thefour parameter logistic equation.

Example 105 Functional Cell-Based Assay

The efficacy of GLP-1 receptor agonists was studied in a cAMP functionalassay using either CHO or HEK-293 Cells expressing the cloned humanGLP-1 receptor. GLP-1-expressing cells (10,000 cells per 0.1 mL) wereplated in 96-well plates in Dulbecco's modified eagles media (DMEM)containing 10% fetal bovine serum and penicillin-streptomycin. Followingovernight incubation of cells, media was removed, and compounds (atconcentrations ranging from 0.0001 to 100 μM) were added to monolayercells in Iscove's modified dulbecco's medium (IMDM), 100 μM RO 20-1724PDE inhibitor, 0.1% BSA, 2% DMSO in a final volume of 100 μL, andincubated for 30 min at 37° C. 95% CO₂, 5% CO₂ in a humidifiedincubator. cAMP was quantitated using a homogenous time-resolvedfluorescence detection system (cAMP dynamic, CIS bio International).GLP-1 produced cAMP production dose response curves with EC₅₀ valuesranging from 0.01 μM-100 μM, typically ranging from about 0.02 μM toabout 10 μM. Receptor activation was expressed as percentage relative tomaximal GLP-1-induced cAMP accumulation. Percent GLP-1 activation vscompound concentration dose response curves were generated by fittingthe data using a sigmoidal dose response curve-fitting program (GraphPADPrizm).

The Table below shows EC-50 and activation data for the above exemplarycompounds of the present invention.

Example EC-50 % Example EC-50 % # (nM) activation # (nM) activation 1900 15 2 670 7.8 3 na na 4 3800 20 5 30000 18 6 3600 7.0 7 474 35 8 13464 9 500 54 10 418 51 11 606 71 12 427 61 13 1210 59 14 450 77 15 14599.6 16 657 78 17 699 80 18 270 74.7 19 181 69.9 20 417 83.5 21 399 70.322 891 73.5 23 1280 65.5 24 1600 53.0 25 594 12.0 26 1097 14.0 27 nd Nd28 398 29.0 29 290 17 30 na na 31 1000 13.0 32 700 8.3 33 1300 7.0 34160 31.0 35 1200 16.0 36 660 13.0 37 490 32.0 38 710 32.0 39 130 56.0 401200 34.0 41 430 42.0 42 1000 56.0 43 500 34.0 44 1000 25.0 45 1000 18.046 1000 22.0 47 1200 29.0 48 895 64.0 49 557 57.0 50 1220 49.0 51 82030.0 52 810 33.0 53 1040 52.5 54 1078 11.8 55 216 49.4 56 370 40.1 57570 20.0 58 565 45.0 59 750 52.0 60 1630 62.0 61 850 29.0 62 1000 15.063 476 23.0 64 190 36.0 65 220 32.0 66 950 21.0 67 1150 55.0 68 110033.0 69 574 51.0 70 988 6.9 71 793 49 72 na na 73 na na 74 327 19.0 75244 20 76 1135 8.12 77 1706 53 78 nd nd 79 nd nd 80 66.0 16 81 70.0 2582 nd nd 83 710 18 84 920 43 85 2000 55 86 59.3 58 87 64.5 82 88 nd nd89 nd nd 90 1231 43 91 725 39 92 723 30 93 138 31 94 424 41 95 364 49 96362 8.5 97 38.2 38 98 626 42 99 1000 28 na: Not active in the functionalcell-based assay of Example 105. nd: No data available for this compoundin the functional cell-based assay of Example 105.

The specificity of GLP-1 agonists for GLP-1 receptor was confirmed byperforming the assay with vector-control mock cells which lack thecloned human GLP-1 receptor. All compounds were devoid of cAMPaccumulation in the mock-transfected cell lines.

We claim:
 1. A method of treating hyperglycaemia comprisingadministering to a subject a compound of Formula (I) or apharmaceutically acceptable salt thereof:

wherein R is —(CH₂)_(p)-G¹-L¹-G², wherein L¹ is selected from the groupconsisting of: a direct bond, —CH₂—, —O—, —N(R¹⁶)—, —C(O)—, —CON(R¹⁶)—,—N(R¹⁶)C(O)—, —N(R¹⁶)SO₂—, —SO₂N(R¹⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—,—S(O)₂—, and —C≡C—, wherein R¹⁶ is selected from the group consistingof: -hydrogen, -alkyl, -aryl, -alkylene-aryl; G¹ is selected from thegroup consisting of: alkynylene, arylene, heteroarylene, fusedarylcycloalkylene, fused cycloalkylarylene, fusedcycloalkylheteroarylene, fused heterocyclylarylene, and fusedheterocyclylheteroarylene, wherein G¹ is optionally substituted 1-4times with substituents independently selected from R¹⁰, wherein R¹⁰ isRb, G² is selected from the group consisting of: -aryl, -heteroaryl,-fused arylcycloalkyl, -fused cycloalkylaryl, -fusedcycloalkylheteroaryl, -fused heterocyclylaryl, and -fusedheterocyclylheteroaryl, wherein G² is optionally substituted 1-4 timeswith substituents independently selected from R¹¹, wherein R¹¹ is Rb, R¹is selected from the group consisting of: —CO₂H, —CO₂R¹², —C(O)NH₂,—C(O)NHR¹², -tetrazole, and acid isostere, wherein R¹² is selected fromthe group consisting of: —C₁₋₁₀ alkyl, -cycloalkyl, and -aryl, whereinR¹² is optionally substituted 1-4 times with a group independentlyselected from R^(c); R² is selected from the group consisting of:-hydrogen, -alkyl, -phenyl, -cycloalkyl, -alkylene-cycloalkyl, and-alkylene-phenyl, wherein alkyl, phenyl, and cycloalkyl groups areoptionally substituted 1-4 times with a group independently selectedfrom R^(c); R³ is selected from R^(a); R⁴ is selected from R^(a); and R⁵is -G³-L²-Q²-L³-G⁴, wherein L² and L³ are independently selected fromthe group consisting of: a direct bond, —CH₂—, —O—, —N(R²⁶)—, —C(O)—,—CON(R²⁶)—, —N(R²⁶)C(O)—, —N(R²⁶)CON(R²⁷)—, —N(R²⁶)C(O)O—,—OC(O)N(R²⁶)—, —N(R²⁶)SO₂—, —SO₂N(R²⁶)—, —C(O)—O—, —O—C(O)—, —S—,—S(O)—, —S(O)₂—, and —N(R²⁶)SO₂N(R²⁷)—, wherein R²⁶ and R²⁷ areindependently selected from the group consisting of: hydrogen, -alkyl,-aryl, and -alkylene-aryl, wherein R²⁶ and R²⁷ are optionallysubstituted 1-4 times with R^(c), or R²⁶ and R²⁷ are taken together withthe atoms to which they are attached to form a heterocyclic ring of 5 to7 members containing 0-2 additional heteroatoms independently selectedfrom oxygen, nitrogen, and sulfur; Q² is selected from the groupconsisting of: a direct bond, C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, andC₂₋₁₀ alkynylene, G³ is selected from the group consisting of: -arylene,-cycloalkylene, -heterocyclylene, -heteroarylene, -fusedarylcycloalkylene, -fused cycloalkylarylene, -fusedcycloalkylheteroarylene, -fused heterocyclylarylene, and -fusedheterocyclylheteroarylene, wherein G³ is optionally substituted 1-4times with substituents independently selected from R⁸, wherein R⁸ isselected from R^(b), G⁴ is selected from the group consisting of: -aryl,-cycloalkyl, -heterocyclyl, -heteroaryl, -fused arylcycloalkyl, -fusedcycloalkylaryl, -fused cycloalkylheteroaryl, -fused heterocyclylaryl,and -fused heterocyclylheteroaryl, wherein G⁴ is optionally substituted1-4 times with substituents independently selected from R⁹, wherein R⁹is selected from R^(b), Rings B and C are optionally substituted 1-4times with substituents independently selected from the group consistingof R^(b); R^(a) is selected from the group consisting of: a) -hydrogen,b) —S(O)_(m)R^(d), c) —S(O)₂OR^(d), d) —S(O)_(m)NR^(d)R^(e), e)—C(O)R^(d), f) —CO₂R^(d), g) —C(O)NR^(d)R^(e), h) -haloalkyl, i)-cycloalkyl, j) -heterocyclyl, k) —C₁₋₁₀ alkyl, l) —C₂₋₁₀ alkenyl, m)—C₂₋₁₀ alkynyl, n) -aryl, o) -heteroaryl, p) —C₁₋₁₀ alkylene-aryl, q)—C₂₋₁₀ alkynylene-aryl, r) —C₁₋₁₀ alkylene-heteroaryl, s) —C₂₋₁₀alkynylene-heteroaryl, and t) —C(R^(f)R^(g))_(n)-aryl, wherein alkyl,alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, and cycloalkyl groupsare optionally substituted 1-4 times with a group independently selectedfrom R^(e); R^(b) is selected from the group consisting of: a)-cycloalkyl, b) -cyano, c) —OR^(d), d) —NO₂, e) -halogen, f)—S(O)_(m)R^(d), g) —SR^(d), h) —S(O)₂OR^(d), i) —S(O)_(m)NR^(d)R^(e), j)—NR^(d)R^(e), k) —O(CR^(f)R^(g))_(n)NR^(d)R^(e), l) —C(O)R^(d), m)—CO₂R^(d), n) —OC₂(CR^(f)R^(g))—CONR^(d)R^(e), o) —OC(O)R^(d), p)—C(O)NR^(d)R^(e), q) —NR^(d) C(O)R^(e), r) —OC(O)NR^(d)R^(e), s) —NR^(d)C(O)OR^(e), t) —NR^(d) C(O)NR^(d)R^(e), u) —CF₃, v) —OCF₃, w)-haloalkyl, x) -haloalkoxy, y) —C₁₋₁₀ alkyl, z) —C₂₋₁₀ alkenyl, aa)—C₂₋₁₀ alkynyl, ab) —C₁₋₁₀ alkylene-aryl, ac) —C₁₋₁₀alkylene-heteroaryl, and ad) -heteroaryl, wherein alkyl, alkenyl,alkynyl, aryl, heteroaryl, and cycloalkyl groups are optionallysubstituted 1-4 times with a group independently selected from R^(c)R^(c) is selected from the group consisting of: a) -halogen, b) -amino,c) -carboxy, d) -cyano, e) —C₁₋₄ alkyl, f) —O—C₁₋₄ alkyl, g) —O—CF₃, h)-cycloalkyl, i) —O-cycloalkyl, j) -aryl, k) —C₁₋₄ alkylene-aryl, l)-hydroxy, m) —CF₃, n) -haloalkyl, o) -haloalkoxy, p) —O-aryl, q)-heteroaryl, r) -heteroarylene-C₁₋₁₀ alkyl, s) -heterocyclyl, t)—CO₂—C₁₋₁₀ alkyl, u) —CO₂—C₁₋₁₀ alkyl-aryl, v) -fused arylcycloalkyl, w)-alkynylene-heteroaryl, x) -alkylene-aryl, y) -alkynylene-aryl, z)-nitro, aa) —N(H)—C(O)—C₁₋₆-alkyl, and bb) —S—C₁₋₆-alkyl; R^(d) andR^(e) are independently selected from the group consisting of: hydrogen,C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, —C₁₋₁₀alkylene-cycloalkyl, aryl, heteroaryl, and heterocyclyl, wherein alkyl,alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl groups areoptionally substituted with one to four substituents independentlyselected from R^(c); or R^(d) and R^(e) together with the atoms to whichthey are attached form a heterocyclic ring of 5 to 7 members containing0-2 additional heteroatoms independently selected from oxygen, sulfurand nitrogen and optionally substituted with 1-3 times with R^(c), R^(f)and R^(g) are independently selected from the group consisting of:hydrogen, C₁₋₁₀ alkyl, cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, -carboxy,and aryl, wherein alkyl, cycloalkyl, and aryl groups are optionallysubstituted with one to four substituents independently selected fromR^(c); or R^(f) and R^(g) together with the carbon to which they areattached form a ring of 5 to 7 members containing 0-2 heteroatomsindependently selected from oxygen, sulfur and nitrogen optionallysubstituted with 1-3 times with R^(c); m is an integer from 1 to 2; n isan integer from 1 to 10; and p is an integer from 0 to
 2. 2. The methodof claim 1, wherein R¹ is —CO₂H.
 3. The method of claim 1, wherein R² ishydrogen.
 4. The method of claim 1, wherein p is
 1. 5. The method ofclaim 1, wherein: p is 1; G¹ is a substituted or unsubstituted phenyl;L¹ is selected from the group consisting of a direct bond, —O—, and—N(H)C(O)—; and G² is a phenyl group substituted 1-4 times withsubstituents independently selected from R¹¹, and G² is substituted withat least one substituent selected from the group consisting of: a)—C₁₋₁₀ alkyl, b) -haloalkyl, c) -haloalkoxy, d) —CF₃, e) —OCF₃, f)-halogen, g) —O—R^(d), h) -cyano, i) —C(O)R^(d), j) —NR^(d)R^(e), k)-cycloalkyl, and l) —CO₂R^(d), wherein alkyl and cycloalkyl groups areoptionally substituted 1-4 times with a group independently selectedfrom R^(c).
 6. The method of claim 1, wherein: p is 1; G¹ is asubstituted or unsubstituted phenyl; L¹ is a direct bond; and G² isselected from the group consisting of: indole, pyridine, pyrimidine,quinoline, and isoxazole, wherein G² is optionally substituted orunsubstituted.
 7. The method of claim 1, wherein: p is 1; G¹ is anunsubstituted phenyl; L¹ is a direct bond; and G² is a phenyl,substituted with a cyano group.
 8. The method of claim 1, wherein R³ is—C₁₋₁₀ alkyl substituted with a phenyl group.
 9. The method of claim 1,wherein R³ is selected from the group consisting of—(R)-1-(phenyl)-propyl and —(S)-1-(phenyl)-propyl.
 10. The method ofclaim 1, wherein R⁴ is selected from the group consisting of -hydrogen,—C₁₋₆ alkyl, and —C(O)—C₁₋₆ alkyl.
 11. The method of claim 1, wherein R⁵is -G³-L²-Q²-L³-G⁴, wherein L² is —O—; L³ is a direct bond; Q² is aC₁₋₁₀ alkylene group; G³ is a phenylene group, and G⁴ is a phenyl group,wherein G⁴ is substituted 1-4 times with substituents independentlyselected from R⁹, wherein R⁹ is selected from R^(b), and wherein G⁴ issubstituted with at least one substituent selected from the groupconsisting of: a) —C₁₋₆ alkyl, b) -haloalkyl, c) -halogen, d) -alkoxy,e) -haloalkoxy, f) —CF₃, and g) —O—CF₃.
 12. A method of treatinghyperglycaemia in a human comprising administering to a human a compoundselected from the group consisting of:(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid 4-hydroxy-cyclohexyl ester,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid 3-hydroxy-cyclopentyl ester,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-3-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-((S)-tetrahydro-furan-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-((R)-tetrahydro-furan-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-phenyl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isobutyl ester,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid 2,2-dimethyl-propyl ester,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tetrahydro-pyran-4-yl ester,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclobutanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-isobutyryl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid(S)-2-({(S)-6-Benzenesulfonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopentanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(piperidine-1-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid cyclopropylmethyl ester,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid (R)-(tetrahydro-furan-3-yl) ester,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(furan-2-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3-methyl-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(4-fluoro-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(4-methoxy-benzoyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-trifluoromethyl-benzoyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclohexanecarbonyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(naphthalene-1-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(thiophene-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(5-methyl-isoxazole-3-carbonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(thiophene-2-sulfonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-dimethylcarbamoyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-2-({(S)-6-Benzyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-phenethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(2,4,6-trifluoro-benzoyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(toluene-2-sulfonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-methyl-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-thiophen-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-fluoro-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-({(S)-6-(2-Chloro-benzyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-methoxy-benzyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(6-methyl-pyridin-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-({(S)-6-(6-Bromo-pyridin-2-ylmethyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-(5-cyano-6-methylsulfanyl-pyridin-2-ylmethyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(1H-imidazol-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(1-methyl-1H-imidazol-2-ylmethyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-thiazol-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(pyridine-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-nitro-benzenesulfonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3-nitro-benzenesulfonyl)-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-({(S)-6-(2-Cyano-benzyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopropylmethyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-pyrimidin-2-yl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-(3-thiophen-3-yl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(2,6-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(2,5-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(3-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(4-chloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(4-chloro-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid tert-butyl ester,(S)-2-({(S)-6-Benzoyl-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzyl-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(5,6-dichloro-pyridin-3-ylmethoxy)-phenyl]-2-oxo-6-(thiophene-2-carbonyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-({(S)-3-[4-(3-Chloro-benzyloxy)-phenyl]-2-oxo-6-thiazol-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-7-[(S)-1-Carboxy-2-(4′-cyano-biphenyl-4-yl)-ethylcarbamoyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylicacid isopropyl ester,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(3-phenyl-prop-2-ynyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(2-ethyl-benzyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclopentyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclohexyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-6-cyclobutyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-cyclopentylmethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-(1-phenyl-ethyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-({(S)-6-(2-Acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionicacid,(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionicacid,(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid,(S)-2-{[(3R,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Chloro-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-methoxy-biphenyl-4-yl)-propionicacid,(S)-2-{[(3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-3-(4′-fluoro-biphenyl-4-yl)-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-6-(3,5-dimethyl-isoxazole-4-sulfonyl)-1-methyl-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid,(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionicacid,(R)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid, and(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-[4-(pyridin-4-yloxy)-phenyl]-propionicacid; or a pharmaceutically acceptable salt thereof.
 13. A method oftreating hyperglycaemia in a human comprising administering to a human(S)-2-({(S)-6-benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionicacid or a pharmaceutically acceptable salt thereof.
 14. A method oftreating hyperglycaemia in a human comprising administering to a human(S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-6-pyridin-2-ylmethyl-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionicacid or a pharmaceutically acceptable salt thereof.
 15. A method oftreating hyperglycaemia in a human comprising administering to a human(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid or a pharmaceutically acceptable salt thereof.
 16. A method oftreating hyperglycaemia in a human comprising administering to a human(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3S,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionicacid or a pharmaceutically acceptable salt thereof.
 17. A method oftreating hyperglycaemia in a human comprising administering to a human(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionicacid or a pharmaceutically acceptable salt thereof.